Composite hydrogen-rich material multi-layer delivery system and preparation method and application thereof

Abstract

The invention relates to the technical field of food science and biological medicine, and particularly discloses a composite hydrogen-rich material multi-layer delivery system and a preparation method and application thereof. The composite hydrogen-rich material multi-layer delivery system comprises a core layer, a middle coating layer and a pH response layer which are sequentially stacked from inside to outside. The delivery system provided by the invention has multiple properties of good waterproofness, excellent acid resistance, targeted release and the like, and the bioavailability of an organism on the hydrogen-rich material can be improved. By optimizing multi-stage coating parameters, a preparation method of the delivery system is further provided on the basis of developing a supercritical CO2 auxiliary method and a vacuum impregnation-electrostatic adsorption combined method to prepare the core layer, and a repeatable technical path is provided for large-scale production of the delivery system. The invention is suitable for the fields of increasing bone mineral density and preventing and treating osteoporosis.

Description

Technical Field

[0001] The present invention relates to the technical fields of food science and biomedicine, and specifically discloses a multi-layer delivery system of a composite hydrogen-rich material, a preparation method thereof, and an application thereof. Background Art

[0002] According to epidemiological survey data, osteoporosis in China shows significant age and gender differences. The overall prevalence rate in people over 50 years old reaches 19.2%, including 6.0% in men and 32.1% in women; the prevalence rate in people over 65 years old climbs to 32.0%, and the incidence rate after menopause in women is particularly prominent, reaching 51.6%. At present, the main clinical intervention strategy for osteoporosis includes drug treatment, or basic treatment by supplementing calcium combined with vitamin D, etc. In fact, in many cases, the amount of minerals obtained by the population is not small, but the absorption efficiency of the human body decreases, resulting in the inability of minerals to be absorbed and utilized by the body. For traditional supplementary methods, the human body will have certain side effects. For example, long-term taking of calcium preparations (such as calcium tablets) will cause constipation, abdominal distension, belching, and nausea symptoms, and will also increase the risk of stones. It even interferes with the absorption of other minerals such as iron, zinc, and magnesium, leading to problems such as anemia and decreased immunity.

[0003] Studies have shown that composite hydrogen-rich materials have the effects of promoting bone tissue regeneration and promoting angiogenesis, and can also provide necessary nutrients and oxygen for new bone tissue, thereby accelerating the repair of bone joints. However, conventional composite hydrogen-rich materials generally have characteristics such as low water solubility, poor acid resistance, and poor targeting, resulting in too fast decomposition in the acidic environment of the gastrointestinal tract, and thus low bioavailability of effective hydrogen. Summary of the Invention

[0004] Aiming at the deficiencies of the existing composite hydrogen-rich materials such as insufficient waterproof performance, weak acid resistance, and poor targeted release ability, the present invention adopts a three-layer gradient composite coating system to successfully construct a multi-layer delivery system of a composite hydrogen-rich material with multiple functional advantages, so as to achieve the purpose of improving the bioavailability of hydrogen-rich materials by the body. The present invention further discloses an industrial preparation process of the above multi-layer delivery system of a composite hydrogen-rich material. By optimizing multi-stage coating parameters, a supercritical CO2-assisted method and a combined method of vacuum impregnation - electrostatic adsorption are developed to prepare the core layer and then coat the intermediate layer and enteric coating layer, providing a repeatable technical path for the large-scale production of this delivery system, and showing superior application potential in the fields of improving bone density and osteoporosis intervention.

[0005] To achieve the above invention purpose, the present invention adopts the following technical solutions: In the first aspect, the present invention provides a multi-layer delivery system of a composite hydrogen-rich material, which includes a core layer, an intermediate coating layer, and a pH-responsive layer stacked in sequence from the inside to the outside; The core layer includes aminated mesoporous silica and a composite hydrogen-rich material loaded therein; The intermediate coating layer includes an inulin-modified stearic acid complex; The pH-responsive layer includes a methyl methacrylate-ethyl acrylate copolymer, which is an enteric coating layer.

[0006] The composite hydrogen-rich material multi-layer delivery system provided by the present invention has a three-layer coating system, in which the outer layer is a pH-responsive methyl methacrylate-ethyl acrylate copolymer. With its excellent acid-base buffering ability (stable in the gastric acid environment, dissolution pH threshold around 5.5), it enhances acid resistance and has pH responsiveness, enabling environmentally adaptive release regulation; the intermediate coating layer carries an inulin-modified stearic acid complex to improve its hydrophobicity and interfacial binding stability; the core layer can uniformly coat the composite hydrogen-rich material, effectively protecting the active ingredients and increasing the drug loading capacity. The delivery system provided by the present invention has multiple properties such as good waterproofness, excellent acid resistance, and targeted release, and can achieve the purpose of improving the bioavailability of the hydrogen-rich material in the body.

[0007] Further, the pore diameter of the mesoporous silica is 2 nm - 10 nm, and the average pore volume is 0.8 cm 3 / g - 1.0 cm 3 / g.

[0008] Further, the modified stearic acid is stearic acid graft-modified with polyethylene glycol (PEG), and its grafting rate is 15% - 20%.

[0009] Further, the mass ratio of inulin to modified stearic acid is (7.5 - 8.5):(2.5 - 1.5).

[0010] Further, the methyl methacrylate-ethyl acrylate copolymer is an anionic polymer copolymerized from methyl methacrylate and ethyl acrylate in a molar ratio of 1 - 5:1 - 5.

[0011] In the present invention, the modified stearic acid is exemplified by stearic acid graft-modified with polyethylene glycol (PEG).

[0012] In the present invention, the methyl methacrylate-ethyl acrylate copolymer is exemplified by Eudragit® L100-55, in which the molar ratio of methyl methacrylate to ethyl acrylate is 1:1.

[0013] Further, the mass ratio of the core layer, the intermediate coating layer, and the pH-responsive layer is (73.5 - 85.5):(10 - 20):(4.5 - 7.5).

[0014] Further, calculated as magnesium hydride, the mass percentage of the composite hydrogen-rich material in the core layer is 10% - 30%.

[0015] The core layer provided in the present invention has a high drug loading capacity. The high drug loading capacity can reduce the use of excipients, lower the medication cost, and improve the clinical treatment effect and response efficiency.

[0016] The raw materials of the composite hydrogen-rich material in the present invention may include silica, calcium carbonate, magnesium oxide, and hydrogen in a mass ratio of (60-80):(5-10):(1-10):(5-10).

[0017] The preparation method of the composite hydrogen-rich material in the present invention includes the following steps: S1. Under an inert atmosphere, calcine the silica at 700°C - 800°C for 1h - 3h to obtain primary silica; S2. Under an inert atmosphere, calcine the calcium carbonate at 800°C - 900°C for 1h - 3h to obtain primary calcium carbonate; S3. Under an inert atmosphere, calcine the magnesium oxide at 500°C - 600°C for 1h - 3h to obtain primary magnesium oxide; S4. Mix the primary silica, primary calcium carbonate, and primary magnesium oxide evenly, heat up to 1300min - 1400min, calcine in a hydrogen atmosphere for 30min - 90min, cool, and after pulverizing, mix evenly to obtain the composite hydrogen-rich material.

[0018] The composite hydrogen-rich material may also be a composition including metal hydrides (such as MgH2, NaAlH4), SiO6(OH)4(H2O) 20 and the like.

[0019] In the second aspect, the present invention provides a preparation method of the above-mentioned composite hydrogen-rich material multi-layer delivery system, and the preparation method includes the following steps: Step 1. Mix the composite hydrogen-rich material, template agent, and alcohol solution to obtain a hydrogen-rich material-template agent solution. After adjusting the pH to alkaline, add a silicon source and carry out a condensation reaction. After the reaction ends, perform solid-liquid separation, and calcine and demold the obtained solid phase to obtain mesoporous silica; Step 2. Perform amination modification on the surface of the mesoporous silica to obtain aminated mesoporous silica; Step 3. Place the aminated mesoporous silica in a composite hydrogen-rich material dispersion liquid, perform vacuum impregnation, and supercritical CO2 drying to obtain mesoporous silica loaded with hydrogen-rich material; Step 4. Sequentially form an inulin-modified stearic acid composite layer and a pH-responsive layer on the surface of the mesoporous silica loaded with hydrogen-rich material to obtain a composite hydrogen-rich material multi-layer delivery system.

[0020] In order to increase the drug loading capacity and the activity of the hydrogen-rich material, when preparing the core layer, the composite hydrogen-rich material is filled and compounded twice through in-situ loading and post-treatment adsorption; secondly, the surface of the mesoporous silica is aminated to enhance the adsorption capacity for the hydrogen-rich material through electrostatic interaction; thirdly, after the second filling, supercritical CO2 drying is used to replace the traditional calcination method to seal the pores of the mesoporous silica and avoid the decomposition and inactivation of the hydrogen-rich material due to high-temperature calcination.

[0021] Through the rational design of the preparation method of the multi-layer delivery system of the composite hydrogen-rich material, and by using a three-layer coating system that cooperates with each other through a compatible process, the functional coupling of the rigid protection of the mesoporous silica in the core layer, the hydrophobic targeting of the intermediate coating layer, and the acid-resistant controlled release of the enteric coating layer is realized.

[0022] Further, in step one, the template agent includes cetyltrimethylammonium bromide.

[0023] Further, in step one, in the hydrogen-rich material-template agent solution, the mass concentration of the composite hydrogen-rich material is 10%-30%; the alcohol solution includes an ethanol solution, such as an ethanol-water solution with a volume ratio of 10-50:10-50; the mass-volume ratio of the template agent to the alcohol solution is 1 g / 80 mL - 1 g / 120 mL.

[0024] Further, in step one, the pH of the alkali is 10.3 - 10.7.

[0025] Further, in step one, the silicon source includes tetraethyl orthosilicate.

[0026] Further, in step one, the temperature of the condensation reaction is 22°C - 28°C and the time is 7.5 h - 8.5 h.

[0027] In the present invention, tetraethyl orthosilicate (TEOS) is used as the silicon source, and combined with ammonia water catalysis, a silicon oxygen tetrahedron network is formed, and the pore structure is more stable, with a specific surface area ≥ 900 m 2 / g; in addition, the micelle size can be controlled by adjusting the proportion of ethanol, so that the pore diameter of the obtained mesoporous silica can be adjusted within 2 - 10 nm to adapt to different loading requirements; the micelle is formed by the self-assembly of surfactants in the solution through hydrophobic-hydrophilic interactions to form micelles.

[0028] Further, in step one, the specific steps of the amination modification include: heating the precipitate at a rate of 4°C / min - 6°C / min to 280°C - 320°C, and then heating at a rate of 1.5°C / min - 2.5°C / min to 545°C - 555°C and holding for 4.8 h - 5.2 h, and then cooling to obtain mesoporous silica.

[0029] In the present invention, the template agent is removed in one step by gradient calcination, avoiding acid corrosion and significantly improving the integrity of the pore wall.

[0030] Further, in step two, the mesoporous silica is activated and dispersed in a hydrocarbon solvent. 3-aminopropyltriethoxysilane is added, and the reaction is carried out at 75 °C - 85 °C for 11 h - 13 h in a protective gas atmosphere to obtain amino-functionalized mesoporous silica.

[0031] In the present invention, the hydrocarbon solvent is exemplified by toluene; APTES amino groups are introduced on the surface of the mesoporous silica, turning its surface Zeta potential from about -25 mV to about +15 mV, enhancing the electrostatic adsorption ability for the composite hydrogen-rich material (negatively charged powder).

[0032] Further, in step three, the parameters of the supercritical CO2 drying are a pressure of 10 MPa - 15 MPa, a temperature of 35 °C - 40 °C, and a time of 2 h - 4 h.

[0033] Further, in step four, before forming the inulin-modified stearic acid composite, an interfacial stabilizer is sprayed on the surface of the mesoporous silica loaded with the hydrogen-rich material.

[0034] In the present invention, an intermediate coating layer and a pH-responsive layer are formed by spraying the inulin-modified stearic acid composite and the methyl methacrylate-ethyl acrylate copolymer.

[0035] To improve the deficiency that the multi-layer coating structure is prone to delamination due to the difference in thermal expansion coefficients, the present invention selects Pluronic F127 as the interfacial stabilizer. Taking this as an example, the interfacial peeling strength between the core layer and the intermediate layer is increased to more than 15 Mpa.

[0036] Further, the preparation method of the inulin-modified stearic acid composite includes the following steps: preparing an emulsion from the inulin solution and the modified stearic acid solution, preparing a porous composite, performing surface hydrophobization treatment by the melt-quenching method, and introducing negative charges by plasma treatment to obtain the inulin-modified stearic acid composite.

[0037] Among them, the melt-quenching method includes: melting the modified stearic acid and covering it on the surface of the inulin, and then immersing it in ice water to obtain the hydrophobized inulin-modified stearic acid composite; The plasma treatment includes: treating the hydrophobized inulin-modified stearic acid composite with oxygen plasma to introduce carboxyl groups on the surface.

[0038] The surface of the intermediate coating layer prepared in the present invention carries negative static electricity, with its Zeta potential ≤ -20 mV and contact angle > 110°.

[0039] In a third aspect, the present invention also provides a composite hydrogen-rich material multi-layer delivery system prepared by the preparation method of the composite hydrogen-rich material multi-layer delivery system provided in the first aspect or the composite hydrogen-rich material multi-layer delivery system provided in the second aspect, and its application in the preparation of products for improving osteoporosis or helping to improve bone density.

[0040] Further, the product includes any one of functional foods or health foods.

[0041] In a fourth aspect, the present invention also provides a functional food for improving osteoporosis, which includes 10 parts - 50 parts of the composite hydrogen-rich material multi-layer delivery system provided in the first aspect and 10 parts - 50 parts of inulin.

[0042] Combining the advantages of the composite hydrogen-rich material multi-layer delivery system provided by the present invention in terms of water solubility, acid resistance, and targeting with the effects of the composite hydrogen-rich material in promoting bone tissue regeneration, promoting angiogenesis, and accelerating the repair of bone joints, etc., the composite hydrogen-rich material can be used as a functional food for improving osteoporosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following will briefly introduce the drawings required to be used in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0044] Figure 1 It is the electron microscope image of the composite hydrogen-rich material multi-layer delivery system in Example 1 of the present invention; Figure 2 It is a typical diagram of the cumulative optical density acquisition of the first three vertebral bodies of zebrafish in some groups in Effect Example 2 of the present invention; Figure 3 It is a statistical chart of the average value of the cumulative optical density of the first three vertebral bodies of zebrafish in each group in Effect Example 2 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0045] In order to make the purpose, technical solutions and advantages of the present invention clearer, the following further details the present invention in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0046] To better illustrate what is provided in the embodiments of the present invention, the following further gives examples through embodiments.

[0047] The composite hydrogen-rich material used in the following embodiments of the present invention is made from raw materials in the following weight parts: 60 parts of silica (particle size 100 - 300 μm), 10 parts of calcium carbonate (median particle size 1 - 50 μm), 1 part of magnesium oxide (median particle size 1 - 50 μm) and 10 parts of hydrogen; The preparation method of the composite hydrogen-rich material at least includes the following steps: S1. Calcinate silica at 800 °C in an inert atmosphere for 1 h to obtain primary silica; S2. Calcinate calcium carbonate at 900 °C in an inert atmosphere for 3 h to obtain primary calcium carbonate; S3. Calcinate magnesium oxide at 500 °C in an inert atmosphere for 1 h to obtain primary magnesium oxide; S4. Mix the primary silica, primary calcium carbonate and primary magnesium oxide evenly, raise the temperature to 1400 °C at a rate of 10 °C / min, calcinate in a hydrogen atmosphere for 90 min, cool to 30 °C, pulverize to 300 mesh and then mix evenly to obtain the product.

[0048] In the following examples, the composite hydrogen-rich materials prepared with other raw material ratios defined in the present invention can also be used. As long as it is within the scope defined in the present invention, comparable technical effects can be achieved.

[0049] The material of the enteric coating layer is a copolymer of methacrylic acid and ethyl acrylate. In the present invention, Eudragit® L100-55 is taken as an example for illustration; The modified stearic acid is stearic acid grafted with polyethylene glycol (PEG). In the present invention, stearic acid-g-polyethylene glycol (SA-PEG) is taken as an example for illustration, and this SA-PEG is purchased from Sigma-Aldrich.

[0050] Example 1 This example provides a multi-layer delivery system of a composite hydrogen-rich material and its preparation method, and tests the performance of the multi-layer delivery system of the composite hydrogen-rich material and its intermediates. The specific content is as follows: I. This example provides a multi-layer delivery system of a composite hydrogen-rich material, which includes a core layer, an intermediate coating layer and a pH-responsive layer stacked in sequence from the inside to the outside; The core layer includes amino-functionalized mesoporous silica and the composite hydrogen-rich material loaded therein; The intermediate coating layer includes inulin-modified stearic acid complex; The pH-responsive layer includes an enteric coating layer prepared from a copolymer of methacrylic acid and ethyl acrylate; The mass ratio of the core layer, the intermediate coating layer and the pH-responsive layer is 80:14:6.

[0051] II. This example also provides a preparation method of the above multi-layer delivery system of the composite hydrogen-rich material. The preparation method includes the following steps: Step 1: Add 5.0 g of cetyltrimethylammonium bromide and 100 g of composite hydrogen-rich material to 500 mL of ethanol solution in sequence, stir at 40 °C for 30 min until completely dissolved, and stir evenly to obtain a hydrogen-rich material-template agent solution; Add 25% ammonia water to the hydrogen-rich material-template agent solution to adjust the pH to 10.5, and slowly add 25 mL of tetraethyl orthosilicate (TEOS) at a dropping rate of 0.1 mL / min, and react at 25 °C and 800 rpm for 8 hours; Among them, the volume ratio of ethanol to water in the ethanol solution is 50:50; Centrifuge the reaction solution after the above reaction at 8000 rpm for 10 min, collect the precipitate, and wash it alternately with 99.5% ethanol / water 3 times to remove unreacted substances; Lay the washed precipitate evenly in a ceramic crucible according to the requirement of thickness ≤ 2 mm, place it in a muffle furnace, heat it to 300 °C at a rate of 5 °C / min, then heat it to 550 °C at a rate of 2 °C / min and keep it warm for 5 h, and naturally cool it to 200 °C and take it out of the muffle furnace to obtain 109.2 g of mesoporous silica. After measurement, the pore diameter of 90% of the samples in this mesoporous silica is in the range of 2 nm - 5 nm, the average pore volume is 1.0 cm 3 / g, and the specific surface area is 1011.1 m 2 / g.

[0052] Step 2: Take 2 g of the above mesoporous silica and place it in a vacuum drying oven, dehydrate it at 120 °C for 2 hours to open the active sites of silanol groups to obtain activated mesoporous silica; Take the above activated mesoporous silica, disperse it in 100 mL of anhydrous toluene, add 1 mL of 3-aminopropyltriethoxysilane (APTES), reflux and react at 80 °C for 12 h under nitrogen protection, centrifuge at 8000 rpm for 10 min, wash it with 99.5% ethanol 3 times, and vacuum dry it at 60 °C for 6 h to obtain amino-functionalized mesoporous silica (NH2-MSN); Step 3: Place the amino-functionalized mesoporous silica in 100 mL of composite hydrogen-rich material dispersion liquid, evacuate, keep it at a pressure of -0.09~-0.1 MPa for 30 min, and then carry out supercritical CO2 drying to obtain mesoporous silica loaded with hydrogen-rich material, that is, the core layer, denoted as core layer I; Among them, the concentration of the composite hydrogen-rich material dispersion liquid is 5%, and the solvent is anhydrous ethanol; During supercritical CO2 drying, the CO2 pressure is 12 MPa, the temperature is 38 °C, and the drying time is 3 h.

[0053] Step 4. Spray Pluronic F127 with a mass concentration of 0.1% on the surface of the mesoporous silica loaded with hydrogen-rich material. After heat treatment at 80 °C for 1 hour, spray the inulin-modified stearic acid composite solution (the solvent is ethanol:water = 7:3 (v / v), and the solid content is 8%) to form a hydrophobic layer with a contact angle of 115°. Use a fluidized bed to spray the Eudragit ® L100-55 solution (the solvent is 95% ethanol, and the solid content is 10%) to obtain a multi-layer delivery system of composite hydrogen-rich materials, denoted as Delivery System I.

[0054] Among them, the preparation method of the inulin-modified stearic acid composite is as follows: Step 1. Dissolve 8 g of inulin in 80 mL of deionized water and stir at 50 °C for 30 min until the inulin is completely dissolved to obtain an inulin solution; Dissolve 2 g of SA-PEG in 20 mL of ethyl acetate and stir at 40 °C for 15 min until the modified stearic acid is completely dissolved to obtain a modified stearic acid solution; Step 2. Slowly add the stearic acid solution to the inulin aqueous solution, and at the same time stir at a high speed of 1000 rpm for 20 min to form a coarse emulsion; Transfer the coarse emulsion to a high-pressure homogenizer and circulate it 3 times under a pressure of 60 MPa to obtain a nano-emulsion. After measurement, its particle size ≤ 200 nm; Step 3. Place the above nano-emulsion in a rotary evaporator and rotate and evaporate it under reduced pressure at 50 °C for 30 min. After removing the solvent, freeze-dry it to obtain a porous composite powder; Step 4. Place the composite powder in an oven and heat it at 80 °C for 1 h to melt the stearic acid and uniformly cover the surface of the inulin; then quickly immerse the sample in ice water for quenching to solidify the stearic acid hydrophobic layer to obtain a quenched composite; Step 5. Place the quenched composite in an oxygen plasma reaction chamber (power 50 W, time 5 minutes), and then immerse it in a NaOH solution with pH 9.0 for 5 min to obtain the inulin-modified stearic acid composite, denoted as Inulin-Modified Stearic Acid Composite I, as the raw material for the inulin-modified stearic acid composite layer.

[0055] III. Performance Testing (1) In this example, the microstructure of Delivery System I was measured, and its electron microscope image is as Figure 1 shown.

[0056] It can be Figure 1 seen from the figure that the delivery system has a porous structure, with an average particle size of about 2 μm and a certain degree of polydispersity.

[0057] (2) In order to evaluate the performance of Core Layer I in terms of drug loading capacity and stability, etc., in this example, other methods were also used to prepare the core layer. The specific method is as follows: A. Preparation of Core Layer Pair Ⅰ The preparation method of the core layer pair Ⅰ is basically the same as that of the core layer Ⅰ (i.e., steps one to three), except that in step three, "performing supercritical CO2 drying" is replaced by "high-temperature calcination", and the remaining steps and their parameter settings are the same as those of the preparation method of the core layer Ⅰ. The finally prepared core layer is denoted as the core layer pair Ⅰ.

[0058] Among them, the conditions for high-temperature calcination are: heating to 300 °C at a rate of 2 °C / min, then heating to 550 °C at a rate of 5 °C / min and holding for 3 h, and naturally cooling to 200 °C and then taking it out.

[0059] B. Preparation of Core Layer Pair Ⅱ The preparation method of the core layer pair Ⅱ is basically the same as that of the core layer Ⅰ (i.e., steps one to three), except that after "obtaining activated mesoporous silica" in step two, no amination modification is carried out, and step five is directly carried out. At the same time, "aminated mesoporous silica" in step five is replaced by "activated mesoporous silica", and the remaining steps and their parameter settings are the same as those of the preparation method of the core layer Ⅰ. The finally prepared core layer is denoted as the core layer pair Ⅱ.

[0060] In this part, the hydrogen-rich material loading rates of the core layer Ⅰ, the core layer pair Ⅰ, and the core layer pair Ⅱ were compared, and the Zeta potentials of the mesoporous silica / aminated mesoporous silica of the core layer Ⅰ and the core layer pair Ⅱ before the secondary filling of the hydrogen-rich material were measured. The specific results are shown in Tables 1 to 2.

[0061] Table 1

[0062] Table 2

[0063] As can be seen from Table 1-2, the amino-functionalized mesoporous silica is positively charged due to the protonation of surface amino groups. After amino-functionalization, the drug loading rate can be significantly improved. In addition, compared with the supercritical CO2 drying provided by the present invention, high-temperature calcination results in a decrease in the loading rate. The specific analysis is as follows: The drug loading amount of Core Layer I (amino-functionalized modification) (20%) is much higher than that of the unmodified Core Layer II (8%), indicating that the amino group (-NH2) enhances the loading efficiency of magnesium hydride through chemical bonding (such as hydrogen bonding or electrostatic attraction). The drug loading amount of Core Layer I (high-temperature calcination) (12%) is lower than that of Core Layer I (20%) because the calcination process may damage the mesoporous structure (such as pore collapse or specific surface area reduction), resulting in a decrease in the loading capacity. The amino-functionalized mesoporous silica is positively charged due to the protonation of surface amino groups, and there may be strong electrostatic adsorption with hydrogen-rich materials (such as the negative charge on the surface of MgH2), thereby promoting loading. However, the surface silanol groups (Si-OH) of the activated mesoporous silica are negatively charged under neutral pH conditions, resulting in electrostatic repulsion with hydrogen-rich materials and a decrease in the loading rate.

[0064] (3) In this example, inulin and SA-PEG were compounded at a mass ratio of 8:2, and an inulin-modified stearic acid control sample was prepared by simple mixing, denoted as Inulin-Modified Stearic Acid Composite Pair I. Further, the contact angles and Zeta potentials of Inulin-Modified Stearic Acid Composite I and Inulin-Modified Stearic Acid Composite Pair I were compared, as follows: Contact angle test method: Press the composite powder into a tablet (pressure 10 MPa, pressure holding for 5 min), or coat it into a film (thickness 50 μm); drop 2 μL of deionized water and measure the contact angle.

[0065] Zeta potential detection method: Disperse the composite at 0.1 wt% in deionized water, ultrasonically treat it for 10 min, and measure the Zeta potential.

[0066] The detection results of the contact angles and Zeta potentials of the two composites are shown in Table 3.

[0067] Table 2

[0068] As can be seen from Table 3, the contact angle of the inulin-modified stearic acid complex prepared only by simple physical mixing with respect to I is <90°, showing hydrophilic characteristics, and the surface charge depends on the natural negative charge of inulin, with a Zeta potential of only -7.5 ± 2.5 mV. For the inulin-modified stearic acid complex I prepared by the emulsion-phase separation method, the contact angle of the inulin-modified stearic acid complex I is >110°, and the modified stearic acid can form a continuous hydrophobic layer through the melt-quenching process; in addition, by introducing carboxyl groups through plasma, the charge density can be doubled, and the Zeta potential can be increased to -22 mV. In addition, since homogenization is carried out in the preparation of the inulin-modified stearic acid complex I in the present invention, agglomeration of the modified stearic acid during simple physical mixing of inulin and the modified stearic acid can be avoided, and the interfacial binding stability can be improved.

[0069] Example 2 This example provides a multi-layer delivery system for a composite hydrogen-rich material, which includes a core layer, an intermediate coating layer, and a pH-responsive layer stacked in sequence from the inside to the outside; The core layer includes amino-functionalized mesoporous silica and the composite hydrogen-rich material loaded therein; The intermediate coating layer includes an inulin-modified stearic acid complex; The pH-responsive layer includes an enteric coating layer prepared from a copolymer of methacrylic acid and ethyl acrylate; The mass ratio of the core layer, the intermediate coating layer, and the pH-responsive layer is 85.5:10:4.5.

[0070] Second, this example also provides a preparation method for the above multi-layer delivery system for a composite hydrogen-rich material. The preparation method includes the following steps: Step 1: Add 5.0 g of cetyltrimethylammonium bromide and 40 g of the composite hydrogen-rich material to 400 mL of an ethanol solution in sequence, stir at 40 °C for 30 min until completely dissolved, and stir evenly to obtain a hydrogen-rich material-template agent solution; Add ammonia water with a concentration of 28% to the hydrogen-rich material-template agent solution, adjust the pH to 10.7, and slowly add 10 mL of tetraethyl orthosilicate (TEOS) at a dropping rate of 0.1 mL / min, and react at 28 °C and 800 rpm for 7.5 hours; The volume ratio of ethanol to water in the ethanol solution is 40:50; Centrifuge the reaction solution after the above reaction at 8000 rpm for 10 min, collect the precipitate, and wash it 3 times alternately with ethanol / water to remove unreacted substances; The above-mentioned washed precipitate was evenly spread in a ceramic crucible according to the requirement of thickness ≤ 2 mm, placed in a muffle furnace, heated to 280 °C at a rate of 4 °C / min, then heated to 555 °C at a rate of 2.5 °C / min and held for 4.8 h, and naturally cooled to 200 °C and taken out from the muffle furnace to obtain 44.6 g of mesoporous silica. It was determined that the pore diameter of 90% of the samples in this mesoporous silica was in the range of 2 nm - 5 nm, the average pore volume was 0.8 cm 3 / g, and the specific surface area was 851.1 m 2 / g.

[0071] Step 2: Take 2 g of the above-mentioned mesoporous silica and place it in a vacuum drying oven, dehydrate at 120 °C for 2 hours to open the active sites of silanol groups, and obtain activated mesoporous silica; Take the above-mentioned activated mesoporous silica, disperse it in 100 mL of anhydrous toluene, add 1 mL of 3-aminopropyltriethoxysilane (APTES), under nitrogen protection, reflux at 75 °C for 13 h, centrifuge at 8000 rpm for 10 min, wash with 99.5% ethanol 3 times, and vacuum dry at 60 °C for 6 h to obtain amino-functionalized mesoporous silica (NH2-MSN); Step 3: Place the amino-functionalized mesoporous silica in 100 mL of a composite hydrogen-rich material dispersion, evacuate, keep it at a pressure of -0.09~-0.1 MPa for 30 min, and then perform supercritical CO2 drying to obtain mesoporous silica loaded with hydrogen-rich material, that is, the core layer, denoted as core layer II; Among them, the concentration of the composite hydrogen-rich material dispersion is 5%, and the solvent is anhydrous ethanol; During supercritical CO2 drying, the CO2 pressure is 15 MPa, the temperature is 35 °C, and the drying time is 4 h.

[0072] It was determined that, calculated by magnesium hydride, the loading rate of the core layer II for the hydrogen-rich material was 20%.

[0073] Step 4: Spray 0.1% Pluronic F127 by mass concentration on the surface of the mesoporous silica loaded with hydrogen-rich material, heat-treat at 80 °C for 1 hour, then spray inulin-modified stearic acid complex (the solvent is ethanol:water = 7:3 (v / v), and the solid content is 8%) to form a hydrophobic layer with a contact angle of 110°, and use a fluidized bed to spray Eudragit ® L100-55 solution (the solvent is 95% ethanol, and the solid content is 10%) to obtain a composite hydrogen-rich material multi-layer delivery system, denoted as composite hydrogen-rich material multi-layer delivery system II.

[0074] Among them, the preparation method of the inulin-modified stearic acid complex is basically the same as that in Example 1, the only difference being that the mass ratio of inulin to SA-PEG is adjusted to 7.5:2.5, and the remaining steps and parameters are the same.

[0075] Example 3 This example provides a multi-layer delivery system for a composite hydrogen-rich material, which includes a core layer, an intermediate coating layer, and a pH-responsive layer stacked in sequence from the inside out; The core layer includes amino-functionalized mesoporous silica and a composite hydrogen-rich material loaded therein; The intermediate coating layer includes an inulin-modified stearic acid complex; The pH-responsive layer includes an enteric coating layer prepared from a methacrylic acid-ethyl acrylate copolymer; The mass ratio of the core layer, the intermediate coating layer, and the pH-responsive layer is 73.5:20:6.5.

[0076] Second, this example also provides a preparation method for the above multi-layer delivery system of the composite hydrogen-rich material. The preparation method includes the following steps: Step 1: Add 5.0 g of cetyltrimethylammonium bromide and 180 g of the composite hydrogen-rich material to 600 mL of an ethanol solution in sequence, stir at 40 °C for 30 min until completely dissolved, and stir evenly to obtain a hydrogen-rich material-template agent solution; Add ammonia water with a concentration of 27% to the hydrogen-rich material-template agent solution, adjust the pH to 10.3, and slowly add 45 mL of tetraethyl orthosilicate (TEOS) at a dropping rate of 0.1 mL / min, and react at 22 °C and 800 rpm for 8.5 hours; Among them, the volume ratio of ethanol to water in the ethanol solution is 50:40; Centrifuge the reaction solution after the above reaction at 8000 rpm for 10 min, collect the precipitate, and wash it 3 times alternately with ethanol / water to remove unreacted substances; Lay the washed precipitate evenly in a ceramic crucible according to the requirement that the thickness ≤ 2 mm, place it in a muffle furnace, heat it to 320 °C at a rate of 6 °C / min, then heat it to 545 °C at a rate of 1.5 °C / min and keep it warm for 5.2 h, and naturally cool it to 200 °C and take it out of the muffle furnace to obtain 196.3 g of mesoporous silica. It is measured that the pore diameter of 90% of the samples in this mesoporous silica is in the range of 2 nm - 5 nm, the average pore volume is 1 cm 3 / g, and the specific surface area is 943.2 m 2 / g.

[0077] Step 2: Take 2 g of the above mesoporous silica and place it in a vacuum drying oven, dehydrate it at 120 °C for 2 hours to activate the silicon hydroxyl active sites and obtain activated mesoporous silica; Take the above-activated mesoporous silica, disperse it in 100 mL of anhydrous toluene, add 1 mL of 3-aminopropyltriethoxysilane (APTES), under nitrogen protection, reflux at 85 °C for 11 h, centrifuge at 8000 rpm for 10 min, wash with 99.5% ethanol three times, and dry in vacuum at 60 °C for 6 h to obtain amino-functionalized mesoporous silica (NH2-MSN). Step 3: Place the amino-functionalized mesoporous silica in 100 mL of a composite hydrogen-rich material dispersion, evacuate, maintain at a pressure of -0.09 to -0.1 MPa for 30 min, and then perform supercritical CO2 drying to obtain mesoporous silica loaded with a hydrogen-rich material, which is the core layer, denoted as core layer III. Among them, the concentration of the composite hydrogen-rich material dispersion is 5%, and the solvent is anhydrous ethanol. During supercritical CO2 drying, the CO2 pressure is 10 MPa, the temperature is 40 °C, and the drying time is 2 h.

[0078] It was determined that, calculated based on magnesium hydride, the loading rate of the hydrogen-rich material in core layer III was 25%.

[0079] Step 4: Spray 0.1% Pluronic F127 by mass concentration on the surface of the mesoporous silica loaded with the hydrogen-rich material. After heat treatment at 80 °C for 1 hour, spray the inulin-modified stearic acid complex (the solvent is ethanol:water = 7:3 (v / v), and the solid content is 8%) to form a hydrophobic layer with a contact angle of 100°. Use a fluidized bed to spray the Eudragit ® L100-55 solution (the solvent is 95% ethanol, and the solid content is 12%) to obtain a composite hydrogen-rich material multi-layer delivery system, denoted as composite hydrogen-rich material multi-layer delivery system III.

[0080] Among them, the preparation method of the inulin-modified stearic acid complex is basically the same as that in Example 1, except that the mass ratio of inulin to SA-PEG is adjusted to 8.5:1.5, and the remaining steps and parameters are the same.

[0081] Example 4 This example provides a composite hydrogen-rich material multi-layer delivery system, which includes a core layer, an intermediate coating layer, and a pH-responsive layer stacked in sequence from the inside to the outside; The core layer includes amino-functionalized mesoporous silica and a composite hydrogen-rich material loaded therein; The intermediate coating layer includes an inulin-modified stearic acid complex; The pH-responsive layer includes an enteric coating layer prepared from a methacrylic acid-ethyl acrylate copolymer; The mass ratio of the core layer, the intermediate coating layer, and the pH-responsive layer is 80.5:12:7.5.

[0082] II. This embodiment also provides a preparation method for the above-mentioned multi-layer delivery system of composite hydrogen-rich materials. The preparation method includes the following steps: Step 1: Add 5.0 g of cetyltrimethylammonium bromide and 125 g of composite hydrogen-rich materials to 500 mL of ethanol solution in sequence, stir at 40 °C for 30 min until completely dissolved, and stir evenly to obtain a hydrogen-rich material-template agent solution; Add ammonia water with a concentration of 26% to the hydrogen-rich material-template agent solution, adjust the pH to 10.6, and slowly add 30 mL of tetraethyl orthosilicate (TEOS) at a dropping rate of 0.1 mL / min, and react at 24 °C and 800 rpm for 8 hours; Among them, the volume ratio of ethanol to water in the ethanol solution is 20:30; Centrifuge the reaction solution after the above reaction at 8000 rpm for 10 min, collect the precipitate, and wash it alternately with ethanol / water 3 times to remove unreacted substances; Lay the washed precipitate evenly in a ceramic crucible according to the requirement of thickness ≤ 2 mm, place it in a muffle furnace, heat it to 300 °C at a rate of 5 °C / min, then heat it to 550 °C at a rate of 1.5 °C / min and keep it for 5 h, and naturally cool it to 200 °C and take it out of the muffle furnace to obtain 136.7 g of mesoporous silica. After measurement, the pore diameter of 90% of the samples in this mesoporous silica is in the range of 2 nm - 5 nm, the average pore volume is 0.85 cm 3 / g, and the specific surface area is 995 m 2 / g.

[0083] Step 2: Take 2 g of the above-mentioned mesoporous silica and place it in a vacuum drying oven, dehydrate it at 120 °C for 2 hours to open the active sites of silanol groups to obtain activated mesoporous silica; Take the above-mentioned activated mesoporous silica, disperse it in 100 mL of anhydrous toluene, add 1 mL of 3-aminopropyltriethoxysilane (APTES), reflux and react at 80 °C for 12 h under nitrogen protection, centrifuge at 8000 rpm for 10 min, wash it 3 times with 99.5% ethanol, and vacuum dry it at 60 °C for 6 h to obtain amino-functionalized mesoporous silica (NH2-MSN); Step 3: Place the amino-functionalized mesoporous silica in 100 mL of composite hydrogen-rich material dispersion, evacuate, keep it at a pressure of -0.09 ~ -0.1 MPa for 30 min, and then carry out supercritical CO2 drying to obtain mesoporous silica loaded with hydrogen-rich materials, that is, the core layer, denoted as core layer Ⅳ; Among them, the concentration of the composite hydrogen-rich material dispersion is 5%, and the solvent is anhydrous ethanol; During supercritical CO2 drying, the CO2 pressure is 13 MPa, the temperature is 37 °C, and the drying time is 3 h.

[0084] It was determined that the hydrogen-rich material loading rate of the core layer Ⅳ was 23% based on magnesium hydride.

[0085] Step 4: Spray a 0.1% Pluronic F127 solution on the surface of the mesoporous silica loaded with the hydrogen-rich material. After heat treatment at 80 °C for 1 hour, spray the inulin-modified stearic acid complex (the solvent is ethanol:water = 7:3 (v / v), and the solid content is 8%) to form a hydrophobic layer with a contact angle of 100°. Then use a fluidized bed to spray the Eudragit ® L100-55 solution (the solvent is 95% ethanol, and the solid content is 12%) to obtain a multi-layer delivery system of the composite hydrogen-rich material, denoted as the multi-layer delivery system Ⅳ of the composite hydrogen-rich material.

[0086] Among them, the preparation method of the inulin-modified stearic acid complex is basically the same as that in Example 1, except that the mass ratio of inulin to SA-PEG is adjusted to 8:2, and the remaining steps and parameters are the same.

[0087] Example 5 This example provides a composite hydrogen-rich material composition, and its preparation method includes: mixing 50 parts of inulin and 50 parts of the multi-layer delivery system of the composite hydrogen-rich material prepared in Example 1, and uniformly mixing them to obtain the composite hydrogen-rich material composition, denoted as Composition Ⅰ.

[0088] Example 6 This example provides a composite hydrogen-rich material composition, and its preparation method includes: mixing 50 parts of inulin and 25 parts of the multi-layer delivery system of the composite hydrogen-rich material prepared in Example 2, and uniformly mixing them to obtain the composite hydrogen-rich material composition, denoted as Composition Ⅱ.

[0089] Example 7 This example provides a composite hydrogen-rich material composition, and its preparation method includes: mixing 50 parts of inulin and 10 parts of the multi-layer delivery system of the composite hydrogen-rich material prepared in Example 3, and uniformly mixing them to obtain the composite hydrogen-rich material composition, denoted as Composition Ⅲ.

[0090] Example 8 This example provides a composite hydrogen-rich material composition, and its preparation method includes: mixing 10 parts of inulin and 50 parts of the multi-layer delivery system of the composite hydrogen-rich material prepared in Example 3, and uniformly mixing them to obtain the composite hydrogen-rich material composition, denoted as Composition Ⅳ.

[0091] Example 9 This example provides a composite hydrogen-rich material composition, and its preparation method includes: mixing 10 parts of inulin and 20 parts of the multi-layer delivery system of the composite hydrogen-rich material prepared in Example 3, and uniformly mixing them to obtain the composite hydrogen-rich material composition, denoted as Composition Ⅴ.

[0092] Comparative Example 1 This comparative example provides a multi-layer delivery system for a composite hydrogen-rich material. This delivery system is basically the same as the delivery system provided in Example 1, except that: (1) "SA-PEG" is replaced with an equal amount of "stearic acid"; (2) "Eudragit L100-55" is replaced with an equal amount of the traditional enteric coating material Eudragit L100, and the remaining raw materials are the same as those in Example 1. This comparative example also provides a preparation method for this multi-layer delivery system for a composite hydrogen-rich material. In its preparation method, except that the raw materials of stearic acid and the pH-responsive layer are different, the remaining parameters are the same as those in Example 1. The finally prepared multi-layer delivery system for a composite hydrogen-rich material is denoted as Delivery System Pair Ⅰ.

[0093] Comparative Example 2 This comparative example provides a composite hydrogen-rich material composition. Its preparation method includes: mixing 50 parts of inulin and 50 parts of the raw material composite hydrogen-rich material in Example 1, and uniformly mixing them to obtain the composite hydrogen-rich material composition, denoted as Composition Pair Ⅰ.

[0094] Effect Example 1 The present invention investigated the performance of Delivery System Ⅰ and Delivery System Pair Ⅰ in terms of acid resistance, hydrogen leakage, enteric release rate, and stability, etc. The specific contents are as follows: (1) Acid resistance test method: Immerse in simulated gastric juice (pH 1.2, 0.1M HCl), and observe the disintegration time of the material.

[0095] (2) Hydrogen leakage test method: Use gas chromatography to measure the amount of hydrogen escaping within 24 hours at 37°C.

[0096] (3) Enteric release rate test method: According to the USP standard, measure the release amount in 8 hours in pH 6.8 phosphate buffer solution.

[0097] (4) Long-term stability test method: Under the conditions of 40°C ± 2°C and 75% RH ± 5% RH (ICH accelerated conditions), through high-temperature and high-humidity accelerated degradation reaction, predict the long-term stability. Time points: Usually 0, 1, 2, 3, 6 months.

[0098] Through the acid resistance test, it can be seen that the hydrophobic layer of the modified stearic acid effectively blocks the penetration of acid solution. The acid resistance time of Delivery System I reaches 2 h, while the control group disintegrates in only 1 h due to the defect of the hydrophobic layer; through the hydrogen leakage test, it can be seen that the modified stearic acid composite layer has high compactness, and the leakage rate is only 0.8%; the leakage rate of the control group is 3.5% due to interface delamination; through the enteric release rate test, it can be seen that Delivery System I is precisely dissolved due to the pH-responsive layer (Eudragit L100-55), and the release rate is 92%; in Control Group 1, Eudragit L100 (with a higher dissolution pH threshold) is used, and the release rate is only 80%. Through the long-term stability test, it can be seen that after 30 days of accelerated aging, the loading rate of Delivery System I remains 95% (the amino modification enhances the interfacial binding), while in the control group, the loading rate drops to 70% due to the poor compatibility between stearic acid and inulin.

[0099] The comparison table of the acid resistance, hydrogen leakage and other indexes of Delivery System I and Delivery System I is shown in Table 3.

[0100] Table 3

[0101] As can be seen from Table 1, within the experimental range of the present invention, compared with Delivery System I, the acid resistance, hydrogen leakage and enteric release rate of Delivery System I are all significantly improved. Among them, the acid resistance time is doubled, the hydrogen leakage rate is reduced by 77%, the enteric release rate is increased by 12%, and the long-term stability is increased by 25%.

[0102] Effect Example 2 The present invention investigated the performance of Compositions I-V and Composition I in increasing bone density, and the specific content is as follows: 1. Detection principle and grouping The bone development of zebrafish is similar to that of humans. Osteoporosis in humans is a systemic bone disease caused by various reasons, which particularly endangers the health and quality of life of the elderly. The present invention uses prednisolone to induce zebrafish to construct an osteoporosis model. After treatment with the test substance, by measuring the cumulative optical density (S) of the first three vertebral bones of zebrafish, it is evaluated whether the test substance has the effect of enhancing bone density.

[0103] In this invention, a blank control group, a model group (methylprednisolone at 25 μg / mL), a positive drug group (etidronate disodium at 300 μg / mL), sample group 1 (composition I at 1.0 g / L), sample group 2 (inulin at 1.0 g / L), sample group 3 (composition pair I at 1.0 g / L), sample group 4 (composition II at 1.0 g / L), sample group 5 (composition III at 1.0 g / L), sample group 6 (composition IV at 1.0 g / L), and sample group 7 (composition V at 1.0 g / L) were set up. Each experimental group had 3 replicates, with 10 zebrafish embryos in each replicate. They were placed in a 24-well plate, and 2 mL of the working solution corresponding to each concentration group was added to each well. The 24-well plate to be tested was placed in a constant temperature incubator at (28.5 ± 0.5) °C. After incubation for 5 days, samples were taken. During the incubation process, the liquid was changed every 6 hours. After the incubation ended, they were stained with 0.2% calcein for 30 min, and then the zebrafish were washed with ultrapure water. 20 zebrafish were randomly selected from each group and photographed using a Nikon fluorescence inverted microscope. The cumulative optical density (S) of the first three vertebral bodies of each fish was statistically analyzed.

[0104] 2. Data analysis method The formula for calculating the promotion rate of cumulative optical density in the bone is shown in Equation 1 as follows: Promotion rate (%) = [(S2 - S1) / (S0 - S1)] × 100% Equation 1 In the formula: S2—the average value of the cumulative optical density of zebrafish in the sample group; S1—the average value of the cumulative optical density of zebrafish in the model group; S0—the average value of the cumulative optical density of zebrafish in the blank control group; A two-tailed T-test was performed on the cumulative optical density of the first three vertebral bodies of zebrafish in the sample group and the cumulative optical density of the first three vertebral bodies of zebrafish in the model group. p <0.05 indicates a significant difference.

[0105] 3. Experimental results The statistical table of the cumulative optical density values and promotion rates of the first three vertebral bodies of zebrafish in some groups (n = 20) is shown in Table 4. The typical graphs of the cumulative optical density collection of the first three vertebral bodies of zebrafish in some groups are as Figure 2 shown, where the yellow dotted line part is the optical density collection area. The statistical graph of the average value of the cumulative optical density of the first three vertebral bodies of zebrafish in each group is as <SHAPE> Figure 3 shown, where the test samples in sample groups 4 - 7 are composition II, composition III, composition IV, and composition V in sequence.

[0106] Table 4

[0107] From Table 4 and Figure 2-3It can be seen that under the conditions of this experiment, compared with the model group, there were significant differences in the promotion rates of the cumulative optical density of the first three vertebral bones of zebrafish at a concentration of 1.0 g / L for Compositions I-V, inulin, and Composition I (p<0.05). Among them, Compositions I-V were 85.6%, 78.1%, 75.3%, 70.2%, and 66.3% respectively, which were significantly higher than inulin (39.3%) and Composition I (55.0%). It can be seen that Compositions I-V have a better effect on increasing bone density than inulin or Composition I.

[0108] For the above reasons, the composite hydrogen-rich material composition provided by the present invention can be used to prepare functional foods for improving osteoporosis or health foods that help improve bone density. Taking this composite hydrogen-rich material composition can avoid the constipation, abdominal distension, belching or nausea symptoms that may occur after long-term taking of calcium tablets; in addition, taking the composite hydrogen-rich material composition will not increase the risk of stones, nor will it interfere with the absorption of other minerals, and it has great application potential.

[0109] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, or improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A multi-layer delivery system for a composite hydrogen-rich material, characterized in that, It includes a core layer, an intermediate coating layer, and a pH-responsive layer that are stacked in sequence from the inside out; The core layer includes aminated mesoporous silica and a composite hydrogen-rich material loaded therein; The intermediate coating layer includes an inulin-modified stearic acid complex; The pH-responsive layer includes a methyl methacrylate-ethyl acrylate copolymer.

2. The composite hydrogen-rich material multi-layer delivery system according to claim 1, wherein The pore diameter of the aminated mesoporous silica is 2 nm - 10 nm, and the average pore volume is 0.8 cm 3 / g - 1.0 cm 3 / g; and / or The modified stearic acid is stearic acid modified by grafting, and its grafting rate is 15%-20%; and / or The mass ratio of the inulin to the modified stearic acid is (7.5-8.5):(2.5-1.5); and / or The methyl methacrylate-ethyl acrylate copolymer is an anionic polymer copolymerized from methyl methacrylate and ethyl acrylate in a molar ratio of 1-5:1-5.

3. The composite hydrogen-rich material multi-layer delivery system according to claim 1, wherein The mass ratio of the core layer, the intermediate coating layer, and the pH-responsive layer is (73.5-85.5):(10-20):(4.5-7.5); Calculated by magnesium hydride, the mass percentage of the composite hydrogen-rich material in the core layer is 10%-30%.

4. The preparation method of the composite hydrogen-rich material multi-layer delivery system according to any one of claims 1-3, characterized in that, The preparation method includes the following steps: Step 1: Mix the composite hydrogen-rich material, the template agent, and an alcohol solution to obtain a hydrogen-rich material-template agent solution. After adjusting the pH to alkaline, add a silicon source and carry out a condensation reaction. After the reaction ends, perform solid-liquid separation, and calcine and demold the obtained solid phase to obtain mesoporous silica; Step 2: Aminate the surface of the mesoporous silica to obtain aminated mesoporous silica; Step 3: Place the aminated mesoporous silica in a composite hydrogen-rich material dispersion, perform vacuum impregnation, and carry out supercritical CO2 drying to obtain mesoporous silica loaded with a hydrogen-rich material; Step 4: Sequentially form an inulin-modified stearic acid composite layer and a pH-responsive layer on the surface of the mesoporous silica loaded with the hydrogen-rich material to obtain a composite hydrogen-rich material multi-layer delivery system.

5. The preparation method of the composite hydrogen-rich material multi-layer delivery system according to claim 4, characterized in that, In Step 1, the template agent includes cetyltrimethylammonium bromide; and / or The mass concentration of the composite hydrogen-rich material in the hydrogen-rich material-template agent solution is 10%-30%; and / or The alkalinity refers to a pH of 10.3-10.7; and / or The silicon source includes tetraethyl orthosilicate; and / or The temperature of the condensation reaction is 22°C-28°C, and the time is 7.5h-8.5h.

6. The preparation method of the composite hydrogen-rich material multi-layer delivery system according to claim 4, characterized in that In Step 1, the specific steps of the calcination and demolding include: heating the obtained solid phase at a rate of 4°C / min-6°C / min to 280°C-320°C, and then heating at a rate of 1.5°C / min-2.5°C / min to 545°C-555°C and holding for 4.8h-5.2h, followed by cooling to obtain mesoporous silica: and / or In Step 2, the specific steps of the amination modification include: activating the mesoporous silica, dispersing it in a hydrocarbon solvent, adding 3-aminopropyltriethoxysilane, and reacting under a protective gas atmosphere at 75°C-85°C for 11h-13h to obtain aminated mesoporous silica; and / or In Step 3, the parameters of the supercritical CO2 drying are a pressure of 10MPa-15MPa, a temperature of 35°C-40°C, and a time of 2h-4h; and / or In Step 4, before forming the inulin-modified stearic acid composite layer, an interfacial stabilizer is sprayed on the surface of the mesoporous silica loaded with the hydrogen-rich material.

7. The preparation method of the composite hydrogen-rich material multi-layer delivery system according to claim 4, characterized in that, The preparation method of the inulin-modified stearic acid complex includes performing surface hydrophobization treatment by the melt-quenching method and introducing negative charges by plasma treatment; Among them, the melt-quenching method includes: melting the modified stearic acid and covering it on the surface of inulin, and then immersing it in ice water to obtain the hydrophobized inulin-modified stearic acid complex; The plasma treatment includes: treating the hydrophobized inulin-modified stearic acid complex with oxygen plasma to introduce carboxyl groups on the surface.

8. Use of the composite hydrogen-rich material multi-layer delivery system according to any one of claims 1-3 or the composite hydrogen-rich material multi-layer delivery system prepared by the preparation method of the composite hydrogen-rich material multi-layer delivery system according to any one of claims 4-7 in the preparation of products for improving osteoporosis or helping to improve bone density.

9. The application according to claim 8, characterized in that, The product includes any one of functional foods or health foods.

10. A functional food for improving osteoporosis, characterized in that, It includes 10 parts - 50 parts of the composite hydrogen-rich material multi-layer delivery system according to any one of claims 1-3 and 10 parts - 50 parts of inulin.

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