A grafted modified mesoporous silica and its preparation method and application

Abstract

The present invention relates to the field of medical drugs and discloses a grafted modified mesoporous silica, a preparation method, and an application thereof. In the grafted modified silica, a digestive enzyme inhibitor is grafted onto the mesoporous silica, the grafting rate of the digestive enzyme inhibitor onto the mesoporous silica is at least 0.1% by weight, and the pore size of the mesoporous silica is 2-200 nm. The digestive enzyme inhibitor and the mesoporous silica work together to effectively reduce the activity of the digestive enzyme inhibitor in the gastrointestinal tract. The large specific surface area of ​​the mesoporous silica helps to improve the utilization rate of the digestive enzyme inhibitor.

Description

Technical Field

[0001] The present invention relates to the field of medical drugs, in particular to a graft-modified mesoporous silica, a preparation method and application thereof, a composition comprising the modified mesoporous silica, and a drug for obesity or diabetes. Background Art

[0002] Obesity refers to a condition characterized by excessive body fat accumulation, potentially negatively impacting health. Obesity is associated with various medical conditions, particularly non-alcoholic steatohepatitis (NASH), type 2 diabetes, cardiovascular disease, obstructive sleep apnea, certain types of cancer, and osteoarthritis. Both obesity and NASH are on the rise worldwide, and conservative treatments, such as lifestyle changes and dietary guidance, are currently ineffective.

[0003] Bariatric surgery is a method for promoting long-term weight loss and treating obesity and NASH. Bariatric surgery primarily works by reducing an individual's energy intake. Energy is absorbed by the body through the following processes: (1) it is ingested as food; (2) the food is broken down and digested by the body's digestive enzymes into small molecules that can be absorbed; and (3) the small molecules that can be absorbed are absorbed by the digestive system (primarily the cells of the gastrointestinal tract wall) and enter the bloodstream. Restricting any of these stages can reduce an individual's energy intake, thereby achieving weight loss, treating obesity, and controlling blood sugar.

[0004] Patent CN113069467A discloses a porous silica material for use as a pharmaceutical or dietary active ingredient. The silica, when ingested, reduces blood lipid and cholesterol concentrations. When used in combination with a related drug, such as orlistat, it can: a) prevent or treat metabolic syndrome (as defined by the International Diabetes Federation), type 2 diabetes, or insulin resistance or hyperglycemia; or (b) reduce blood glucose concentration. The mesoporous silica has a particle size distribution of 300 nm. Particles smaller than this size result in bodily absorption of the silica and increase blood silicon concentration. Particles larger than this size are not associated with bodily absorption and are rapidly excreted from the gastrointestinal tract through the surface. The weight-loss and cholesterol-lowering mechanism of mesoporous silica is based on the adsorption of biomolecules (bile acids, lipids, proteins, and enzymes) and water into the porous matrix of the active porous component or formulation. The active porous component or formulation can be specifically designed to selectively adsorb low-density lipoprotein (LDL) and other gastrointestinal molecules, resulting in reduced activity of encapsulated gastrointestinal molecules, such as lipase and related molecules.

[0005] At present, mesoporous silica and other active drugs are used in combination. For example, the combination of mesoporous silica and the drug molecule orlistat in patent CN113069467A has an effective synergistic effect. Moreover, if the drug molecule is other small molecules, it is also easily absorbed into the blood circulation, which greatly affects the safety performance of the drug preparation. Summary of the Invention

[0006] To this end, it is necessary to provide a grafted modified mesoporous silica and its preparation method, composition and application to enhance the synergistic effect between the digestive enzyme inhibitor and the mesoporous silica, and further reduce the energy absorption of the organism.

[0007] To achieve the above objectives, the present invention provides a grafted modified mesoporous silica, comprising mesoporous silica and a digestive enzyme inhibitor, wherein the digestive enzyme inhibitor is grafted onto the mesoporous silica, the pore size of the mesoporous silica is 2-200 nm, and the grafting rate of the digestive enzyme inhibitor on the mesoporous silica is at least 0.1 wt%.

[0008] The digestive enzyme inhibitors described herein can inhibit the activity of relevant digestive enzymes in the digestive gastrointestinal environment of the human or animal or its simulated environment, reduce the activity of digestive enzymes, and make it difficult for large molecules such as fat or starch to be enzymatically hydrolyzed into small molecules that can be absorbed by the human body.

[0009] Another aspect of the present invention provides a method for preparing graft-modified mesoporous silica, comprising the following steps:

[0010] (1) Preparation of mesoporous silica;

[0011] (2) reacting the mesoporous silica with a digestive enzyme inhibitor so that the digestive enzyme inhibitor is grafted onto the mesoporous silica to obtain graft-modified mesoporous silica.

[0012] Another aspect of the present invention provides a graft-modified mesoporous silica composition, comprising the graft-modified mesoporous silica and a pharmaceutically acceptable excipient.

[0013] Another aspect of the present invention provides the use of graft-modified mesoporous silica or the above-mentioned mesoporous silica composition in the preparation of a drug for regulating the metabolism of obese or diabetic patients.

[0014] Another aspect of the present invention provides a drug for treating obesity or diabetes, the above-mentioned graft-modified mesoporous silica or the above-mentioned mesoporous silica composition.

[0015] The above technical solution has the following beneficial effects:

[0016] (1) Digestive enzyme inhibitors are grafted onto mesoporous silica and, after entering the human body, can synergistically reduce the body's absorption of energy, thereby treating the subject's obesity and diabetes. Specifically, digestive enzyme inhibitors can combine with digestive enzymes in the gastrointestinal tract, reducing the digestive activity of digestive enzymes on nutrients, thereby preventing nutrients from being digested and decomposed into small molecules. After mesoporous silica enters the body, related digestive enzymes or other biological molecules in the gastrointestinal tract can be adsorbed into the pores. After the digestive enzyme molecules are encapsulated in the pores, they will be difficult to contact the decomposition substrate, thereby further avoiding the decomposition of nutrients. The result of the combined action of mesoporous silica and digestive enzyme inhibitors is to reduce the activity of digestive enzymes, thereby playing a role in treating obesity and lowering blood sugar concentrations.

[0017] (2) Mesoporous silica has a high specific surface area. The larger the specific surface area, the more digestive enzyme inhibitors can be grafted onto the mesoporous silica through the silane coupling agent. After the digestive enzyme inhibitors are grafted and evenly distributed onto the mesoporous silica, it may be easier for the digestive enzyme inhibitors to combine with the digestive enzymes in the environment, thereby improving the drug utilization rate of the digestive enzyme inhibitors and further enhancing the effect of treating obesity and controlling blood sugar.

[0018] (3) Mesoporous silica is usually difficult to be absorbed into the blood. In the present invention, after the digestive enzyme inhibitor molecules are grafted and connected to the mesoporous silica, they can effectively prevent the digestive enzyme inhibitors from being absorbed into the blood circulation, ensuring that the digestive enzyme inhibitors can continue to play their role. The digestive enzyme inhibitors are not absorbed into the blood, which also reduces the side effects of the medication and ensures the safety of the medication.

[0019] (4) In the present invention, the silane coupling agent can be further connected with polyethylene glycol, and the polyethylene glycol then reacts with the digestive enzyme inhibitor, so that the modified mesoporous silica has better water solubility and biocompatibility. The use of the linker can also increase the grafting amount of mesoporous silica to a certain extent. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 SEM (1A) and TEM (1B) images of mesoporous silica prepared by static hydrothermal reaction at 100°C in Example 1.

[0021] Figure 2 The mesoporous silica prepared in Example 1, the isotherm (A1) and pore size distribution (A2) of the mesoporous silica at 100°C, and the isotherm (B1) and pore size distribution (B2) of the mesoporous silica synthesized at 120°C.

[0022] Figure 3 This is the reaction scheme of Example 2-4.

[0023] Figure 4This is the reaction scheme of Example 7. DETAILED DESCRIPTION

[0024] The invention discloses a grafted modified mesoporous silica, comprising mesoporous silica and a digestive enzyme inhibitor. The digestive enzyme inhibitor is grafted onto the mesoporous silica, and the grafting rate of the digestive enzyme inhibitor onto the mesoporous silica is at least 0.1 wt%.

[0025] Preferably, the grafting rate of the digestive enzyme inhibitor on the mesoporous silica is 3-12% by weight.

[0026] Advantageously, mesoporous silica has a relatively high specific surface area. By grafting digestive enzyme inhibitors, mesoporous silica can graft digestive enzyme inhibitor molecules. After the digestive enzyme inhibitors are grafted and distributed on the mesoporous silica, they have more opportunities to contact with the digestive enzymes in the gastrointestinal tract, thereby being able to show higher utilization rates.

[0027] In some embodiments, the grafting rate of the digestive enzyme inhibitor onto the mesoporous silica can be, but is not limited to, 0.1-0.5 wt%, 0.5-1 wt%, 0.5-5 wt%, 0.5-10 wt%, 0.5-12 wt%, 1-5 wt%, 1-12 wt%, 3-5 wt%, 3-8 wt%, 3-12 wt%, 5-10 wt%, or 5-12 wt%, or 10-12 wt%. Products with varying grafting rates can be prepared by controlling process conditions such as the grafting reaction time and reaction materials. In other embodiments, the grafting rate of the digestive enzyme inhibitor can exceed 12 wt%.

[0028] The grafting rate of the present invention = (grafted weight of digestive enzyme) / (initial weight of mesoporous silica).

[0029] In the present invention, the pore size of the mesoporous silica is 2-200 nm.

[0030] In some embodiments, the pore size of the mesoporous silica may range from 2-50 nm, 2-100 nm, 2-150 nm, 5-50 nm, 5-100 nm, 5-150 nm, 5-200 nm, 50-100, 100-150 nm, or 150-200 nm.

[0031] Preferably, the pore size of the mesoporous silica is 5-15 nm, which can effectively encapsulate gastrointestinal molecules and work together with the grafted digestive enzyme inhibitors to reduce the individual's digestion and absorption of corresponding nutrients.

[0032] In some embodiments, the pore size of the prepared mesoporous silica can be 5-10 nm, 5-7.5 nm, 7.7-9 nm, 10-15 nm, and the digestive enzyme inhibitor is a glucosidase inhibitor.

[0033] In particular, mesoporous silica with a pore size of 7.5-9.0 nm can specifically encapsulate glucosidase in the gastrointestinal environment. In particular, when the pore size is 9.0 nm, it has a better encapsulation effect on glucosidase. At this time, glucosidase inhibitors are grafted onto the mesoporous silica and combined with the free glucosidase in the unencapsulated environment, making the free glucosidase inactive, thereby comprehensively reducing the activity of glucosidase in the organism.

[0034] In some other embodiments, the digestive enzyme inhibitor may also be other digestive enzyme inhibitors such as amylase inhibitors, lipase inhibitors, etc. When selecting a digestive enzyme inhibitor, it is necessary to select a chemical substance that still has inhibitory activity after grafting reaction with mesoporous silica.

[0035] Amylase inhibitors and glucosidase inhibitors can inhibit the process of breaking down starch or polysaccharides in the gastrointestinal tract into absorbable small molecules, while lipase inhibitors can inhibit the process of fat being enzymatically hydrolyzed into fatty acids and glycerol, and thus can be used to treat obesity.

[0036] In an embodiment of the present invention, the mesoporous silica is grafted with two digestive enzyme inhibitors, which can be of the same or different types, without affecting each other. Different digestive enzyme inhibitors can synergize with each other to jointly reduce individual energy intake.

[0037] Preferably, the glucosidase inhibitor is one or more of the following: acarbose, voglibose, miglitol, emiglitate, canaglibose, pradimicin Q, and salbostatin. Pradimicin Q is described in "PRADIMICIN Q, A NEW PRADIMICIN AGLYCONE, WITH α-GLUCOSIDASE INHIBITORY ACTIVITY," published in the Journal of Antibiotics on September 29, 1992.

[0038] The preparation method of the graft-modified mesoporous silica comprises the following steps:

[0039] (1) Preparation of mesoporous silica;

[0040] (2) reacting the mesoporous silica with a digestive enzyme inhibitor so that the digestive enzyme inhibitor is grafted onto the mesoporous silica to obtain graft-modified mesoporous silica.

[0041] Also included between step (1) and step (2) is step A:

[0042] The mesoporous silica or the digestive enzyme inhibitor is modified using a coupling agent, and then in step (2), the mesoporous silica or the digestive enzyme inhibitor is grafted via the coupling agent.

[0043] After the mesoporous silica or the digestive enzyme inhibitor is modified by the coupling agent, it is convenient for the two to be grafted and coupled.

[0044] Preferably, in step A, the coupling agent is a silane coupling agent, and the amount of the silane coupling agent is 5 mol%-30 mol%.

[0045] In some embodiments, the amount of the silane coupling agent is 5 mol%, 10 mol%, 15 mol%, 20 mol%, or 30 mol%.

[0046] Preferably, the silane coupling agent is a silane coupling agent containing a vinyl group, an amino group, an epoxy group, a methacryloxy group, a mercapto group or a urea group.

[0047] In some embodiments, the silane coupling agent may include silane coupling agent KH151, silane coupling agent KH792, silane coupling agent KH-560, silane coupling agent KH550, and the like.

[0048] When the silane coupling agent reacts, the reaction steps can be: first react with mesoporous silica, then react with polyethylene glycol, or first react with polyethylene glycol, then react with mesoporous silica.

[0049] In the preparation of the above-mentioned mesoporous silica grafted with a digestive enzyme inhibitor, in some embodiments, the silane coupling agent first reacts with a linker, polyethylene glycol, before reacting with the digestive enzyme inhibitor, and then is linked to the digestive enzyme inhibitor via the functional groups on the linker, polyethylene glycol.

[0050] Advantageously, the use of polyethylene glycol as an organic linker to connect the digestive enzyme inhibitor may facilitate the grafting reaction of the digestive enzyme inhibitor and also maintain the physical or chemical properties of the mesoporous silica to a certain extent, which is beneficial for drug development.

[0051] The polyethylene glycol linker is selected to have a linear structure with connecting functional groups at both ends, and the functional groups can be selected from one of the following functional groups: -OH, -COOH, -CN, -NH2, halogen, -CHO, -methanesulfonate, isocyanate, epoxy, NHS, acrylate, thiol, -CONH2, etc.

[0052] The above groups are functional groups modified after the reaction of mesoporous silica with common silane coupling agents. The above active functional groups all have common addition or substitution groups, which are convenient for grafting reaction with digestive enzyme inhibitors.

[0053] In the present invention, the preparation process of mesoporous silica is as follows:

[0054] (1) dissolving the organic pore-forming material in a hydrochloric acid solution and stirring to dissolve;

[0055] (2) After complete dissolution, increase the stirring rate and add the silica source material. After the mixture is stirred and completely dispersed, let it stand for at least 20 hours;

[0056] (3) Then transfer to static hydrothermal reaction under heating for 24 h;

[0057] (4) After the static hydrothermal reaction is completed, the solid is broken up by stirring and naturally cooled to room temperature. The suspension is then filtered and washed to obtain the product mesoporous silica.

[0058] In some embodiments, the heating temperature in step (3) is 100-120°C.

[0059] In some embodiments, the organic pore-forming material is P123 paste, and the silica source material can be selected from tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), tetrapropyl orthosilicate (TPOS), sodium silicate, or a combination of two or more thereof.

[0060] A graft-modified mesoporous silica composition comprises at least one of the above-mentioned graft-modified mesoporous silicas and a pharmaceutically acceptable excipient.

[0061] The above composition may also be mixed with other different lipase inhibitors.

[0062] In some embodiments, the lipase inhibitor is one or more of the following: orlistat, lipstatin, tetrahydrolipstatin, FL-386, WAY-121898, BAY-N-3176, valproate, esterase inhibitor, erbinolactone A, erbinolactone B, RHC 80267, or cetilistat.

[0063] In some embodiments, the pharmaceutically acceptable excipient is selected from fillers, diluents, disintegrants, colorants, lubricants, binders, film formers, wetting agents, emulsifiers, and any mixtures thereof. The above-mentioned graft-modified mesoporous silica or mesoporous silica composition is used in drugs for regulating metabolism in patients with obesity or diabetes.

[0064] A drug for treating obesity or diabetes, comprising any of the above-mentioned graft-modified mesoporous silica or mesoporous silica composition.

[0065] Preferably, the dosage form is a liquid, tablet, caplet or capsule.

[0066] In order to explain the technical content, structural features, achieved objectives and effects of the technical solution in detail, the following is a detailed description in conjunction with specific embodiments.

[0067] In the following examples, unless otherwise specified, the materials used are:

[0068] Silane coupling agent: Silane coupling agent KH-560, 3-(2,3-epoxypropoxy)propyltrimethoxysilane;

[0069] Silane coupling agent KH-550, 3-aminopropyltriethoxysilane;

[0070] The EPO-PEG10-EPO material was polyethylene glycol diglycidyl ether—Sigma Aldrich (average Mn 500).

[0071] 1. Preparation of grafted products

[0072] Example 1 Preparation and Characterization of Mesoporous Silica

[0073] P123 paste (2.66 g) was weighed directly into a 250 mL glass storage bottle using a spatula and a stirring rod was added (the length of the stirring rod should be slightly shorter than the diameter of the reaction bottle / container). Then, 80 mL of 2 M HCl solution and 20 mL of deionized water were poured into the bottle. The mixture was stirred (400 rpm) at 40°C for 4 hours (P123 required ≥ 2 hours to dissolve to provide a transparent translucent solution). The solution was slightly translucent. The stirring rate was increased to 550 to 650 rpm, and then 6.07 mL of TEOS was quickly added to the solution via syringe while stirring at 40°C. The mixture was stirred (550 to 650 rpm) for 10 minutes. The bottle was left to stand in a 40°C water bath for 24 hours (minimum 20 hours required). 25 minutes after the static stage, the mixture turned into a white solid. After the low-temperature reaction was completed, the bottle was transferred to a higher temperature water bath and static hydrothermal reactions (in an oven) were performed at 100 and 120°C for 24 hours, respectively. Finally, the bottle was removed and the hot mixture was stirred at 500 rpm to break up the solids while cooling to 25°C (approximately 1 hour; the bottle cap was loosened). After cooling to room temperature, stirring was continued for 5 minutes, and the resulting suspension was filtered through a Buchner filter. The white filtrate was washed with deionized water (until the pH value of the solid indicated by pH paper was between 5 and 6) and placed on the Buchner filter for several minutes to drain excess water.

[0074] The structure of mesoporous silica obtained by hydrothermal reaction at 100℃ is as follows Figure 1 shown.

[0075] The isotherm curves and pore size distribution of mesoporous silica synthesized at (A) 100℃ and (B) 120℃ are shown in Figure 2. Figure 2 According to our results, the optimal condition for producing mesoporous silica particles with similar properties to those of CN113069467A is a static hydrothermal reaction at 120 °C, which produces particles with a modal pore size of 9 nm.

[0076] The following grafting modification experiments were carried out using the mesoporous silica particles with a modal pore size of 9 nm prepared in Example 1.

[0077] Examples 2-4

[0078] Preparation of acarbose-grafted mesoporous silica:

[0079] 200mg of mesoporous silica was added to a nitrogen-purged flask and 20mL of anhydrous toluene was added. The suspension was stirred at room temperature (400rpm) for 30 minutes under a nitrogen stream. 5, 15 and 30mol% of silane coupling agent KH-560 were added to the mixture and stirred for 5 minutes, then heated at 110°C for 18 hours. The mixture was cooled to room temperature, filtered and washed with toluene and ethanol in turn. The obtained silane-modified mesoporous silica white solid was vacuum dried overnight at 70°C.

[0080] 0.03 M acetic acid (10 ml), the silane-modified mesoporous silica, and acarbose (10 mg) were stirred at room temperature overnight (15 h). The mixture was deacidified and washed with distilled water, followed by drying at 50°C for 4 hours to obtain finished mesoporous silica products with different drug grafting ratios: 0.8 wt%, 2.2 wt%, and 3.6 wt%.

[0081] The preparation route of drug-grafted mesoporous silica is as follows: Figure 3 shown.

[0082] Example 5

[0083] The preparation steps of acarbose-grafted mesoporous silica were different from those in Example 4 except that the amount of acarbose added to the reaction was 20 mg, the reaction time was 24 h, and the grafting rate was 8.4 wt %.

[0084] Example 6

[0085] The preparation steps of acarbose-grafted mesoporous silica were different from those in Example 4 except that the amount of acarbose added to the reaction was 30 mg, the reaction time was 24 h, and the grafting rate was 11.4 wt %.

[0086] Example 7

[0087] Acarbose was grafted onto mesoporous silica via polyethylene glycol. Figure 4 The process shown:

[0088] 200mg of mesoporous silica was added to a nitrogen-purged flask and 20mL of anhydrous toluene was added. The suspension was stirred at room temperature (400rpm) for 30 minutes under a nitrogen stream. 30mol% of silane coupling agent KH-550 was added to the mixture and stirred for 5 minutes, then heated at 110°C for 18 hours. The mixture was cooled to room temperature, filtered and washed with toluene and ethanol in sequence. The obtained silane-modified mesoporous silica white solid was vacuum dried overnight at 70°C.

[0089] 0.03M acetic acid (10 ml), silane-modified mesoporous silica, and polyethylene glycol (20 mg) were stirred and reacted at 60°C for 3 hours. The solution was filtered to remove the acid, washed with distilled water, and then dried at 50°C for 4 hours to obtain polyethylene glycol-modified mesoporous silica.

[0090] 0.03M acetic acid (10 ml), polyethylene glycol-modified mesoporous silica, and acarbose (10 mg) were stirred at room temperature overnight (15 h), deacidified, washed with distilled water, and then dried at 50°C for 4 hours to obtain a mesoporous silica product with a grafting rate of 4.6%.

[0091] Example 8

[0092] The preparation steps of acarbose-grafted mesoporous silica were different from those in Example 7 except that the amount of acarbose added to the reaction was 30 mg, the reaction time was 36 h, and the grafting rate was 14.4 wt %.

[0093] Example 9

[0094] The graft-modified mesoporous silica prepared in Example 4 was mixed with 5% orlistat, a diluent and other auxiliary materials to form a composition.

[0095] control group

[0096] Acarbose and mesoporous silica were mixed, and the mixture contained 2.5% acarbose. 2. Efficacy verification of grafted modified mesoporous silica

[0097] Existing studies have shown that acarbose has inhibitory activity on amylase. In the present invention, the inhibitory activity of modified mesoporous silica on the enzyme is determined by an amylase activity inhibition test.

[0098] 2.1 Amylase digestion test preparation

[0099] 1) Set two water baths to 37 and 95°C.

[0100] 2) 150 mg of soluble starch was dissolved in 100 mL of hot distilled water at 95° C. for 10 minutes, and then cooled to room temperature to prepare a 0.15% soluble starch solution.

[0101] 3) Prepare PBS (pH 5.4) buffer solution using 0.1 M HCl solution and pH 7.4 PBS buffer solution.

[0102] 4) Prepare a 50 μg / ml amylase solution (PBS pH 5.4). (Note: The amylase solution should be used within 3-4 days and stored in the refrigerator.)

[0103] 5) Dissolve 1.4 g of DNS in 2 M NaOH (15 mL) and distilled water (60 mL) to prepare 75 mL of 3,5-dinitrosalicylic acid (DNS) solution.

[0104] 6) Set the wavelength of the UV-visible spectrometer to 540 nm (for amylase testing)

[0105] 2.2 Amylase starch digestion test

[0106] 1) The sample in Example (1 mg in 2 mL pH 5.4 PBS) was stirred at 37°C for 30 minutes, and then an equal volume of porcine α-amylase (50 μg / mL; 2 mL, pH 5.4 PBS) was added.

[0107] 2) The mixture was incubated at 37°C with stirring (500 rpm) for 30 minutes.

[0108] 3) Remove the stirring rod and centrifuge at 3000G for 3 minutes

[0109] 4) The supernatant was filtered through a 0.45 μm pore size filter.

[0110] 5) 3 ml (out of 4 ml) of the supernatant was incubated with soluble starch (1.5 mg / mL; 1.5 mL) at 37° C. with stirring (500 rpm) for 30 minutes.

[0111] 6) DNS solution (3 ml) was added to the mixture and heated at 95°C for 10 minutes.

[0112] 7) The tubes were then cooled in a room temperature water bath for 20 minutes. (The extinction coefficient is temperature dependent; it is important that the samples are at room temperature before taking any measurements.)

[0113] 8) Place the sample in a quartz cuvette (optical path length = 1 cm) and measure the absorbance at 540 nm using UV-visible light analysis. Record the absorbance. (Note: The absorbance of the sample should be measured within 20 minutes, as the absorbance of the same sample will vary over time.)

[0114] 9) Control experiments were performed using amylase and starch (uninhibited enzyme activity) and buffer and starch (no enzyme activity).

[0115] 10) Data processing: UV-visible absorbance at 540 nm indicates the amount of digested starch (reducing sugars) and is related to the amount of amylase present in the supernatant.

[0116] The percentage of α-amylase activity in the supernatant was expressed as [(sample absorbance - starch control absorbance) / (amylase control absorbance - starch control absorbance) × 100%].

[0117] 3. Efficacy Verification of Drug-Grafted Mesoporous Silica

[0118] 3.1 The results of amylase inhibition by mesoporous silica with different pore sizes prepared in Example 1 are shown in Table 1.

[0119] The results in Table 1 show that the mesoporous silica with a modal pore size of 9 nm produced under the hydrothermal reaction conditions of 120°C has a better adsorption effect on amylase.

[0120] Table 1. Amylase activity inhibition effect of mesoporous silica obtained by hydrothermal reaction at different temperatures

[0121]

[0122] 3.2 The samples of Examples 2-7 and the control group were tested for amylase inhibition effect. The test results are shown in Table 2.

[0123] Table 2 Amylase inhibition structures of mesoporous silica with different drug grafting rates.

[0124]

[0125]

[0126] The results in Table 2 show the inhibitory effect of modified mesoporous silica with different acarbose grafting ratios on amylase. Compared to the simple adsorption effect of mesoporous silica, the introduction of acarbose further inhibits the degradation of starch by amylase. As shown by the 2.5% content in the control group and the 2.2% grafting ratio in Example 3, acarbose exhibits higher drug utilization after grafting onto mesoporous silica. This may be due to the high specific surface area of ​​mesoporous silica enabling a more uniform spatial distribution of acarbose, providing more opportunities for contact with amylase. The target products modified within the range of Examples 4 (grafting ratio 3.6% > 3%) to 6 (11.4% < 12%) exhibit sufficient inhibitory activity against amylase. Although further increasing the acarbose grafting ratio may further enhance the inhibitory effect, it also affects the physical and chemical properties of the mesoporous silica to some extent.

[0127] In the present invention, the pores on the mesoporous silica are used to adsorb and encapsulate digestive enzyme molecules in the gastrointestinal tract to prevent the digestive enzyme molecules from contacting the digestive substrate, while the digestive enzyme inhibitor can bind to the active site of the digestive enzyme to reduce the activity of the digestive enzyme. After the mesoporous silica and the digestive enzyme inhibitor are grafted, they can play a synergistic role in the body to jointly reduce the decomposition of the substrate, thereby reducing the absorption of energy molecules by the gastrointestinal environment, playing a role in treating obesity and lowering blood sugar concentration.

[0128] It should be noted that, in this document, relational terms such as first and second, etc., are used solely to distinguish one entity or operation from another, and do not necessarily require or imply any actual relationship or order between these entities or operations. Furthermore, the terms "include," "comprise," or any other variations thereof are intended to encompass non-exclusive inclusion, such that a process, method, article, or terminal device comprising a series of elements includes not only those elements, but also other elements not explicitly listed, or elements inherent to such process, method, article, or terminal device. Without further limitation, elements defined by the phrase "include..." or "comprising..." do not exclude the presence of additional elements in the process, method, article, or terminal device comprising the elements. Furthermore, in this document, "greater than," "less than," "exceeding," etc., are understood to exclude the number itself; "above," "below," "within," etc., are understood to include the number itself.

[0129] Although the above embodiments have been described, those skilled in the art may make additional changes and modifications to these embodiments once they know the basic creative concepts. Therefore, the above descriptions are merely embodiments of the present invention and do not limit the scope of patent protection of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention's description and drawings, or directly or indirectly applied in other related technical fields, are also included in the scope of patent protection of the present invention.

Claims

1. A graft-modified mesoporous silica, characterized in that: The invention comprises mesoporous silica and a digestive enzyme inhibitor, wherein the digestive enzyme inhibitor is grafted onto the mesoporous silica, the grafting rate of the digestive enzyme inhibitor onto the mesoporous silica is at least 0.1% by weight, the pore size of the mesoporous silica is 2-200 nm, and the digestive enzyme inhibitor is a glucosidase inhibitor.

2. The graft-modified mesoporous silica according to claim 1, wherein The grafting rate of the digestive enzyme inhibitor on the mesoporous silica is 3-12% by weight.

3. The graft-modified mesoporous silica according to claim 1, wherein The pore size of the mesoporous silica is 5-15 nm.

4. The graft-modified mesoporous silica according to claim 1, wherein The glucosidase inhibitor is one or more of the following: acarbose, voglibose, miglitol, emiglitate, canaglibose, pranamicin Q, and saboteur.

5. The method for preparing the graft-modified mesoporous silica according to any one of claims 1 to 4, characterized in that: The steps include: (1) Preparation of mesoporous silica; (2) reacting the mesoporous silica with a digestive enzyme inhibitor so that the digestive enzyme inhibitor is grafted onto the mesoporous silica to obtain graft-modified mesoporous silica.

6. The preparation method according to claim 5, wherein Also included between step (1) and step (2) is step A: The mesoporous silica or the digestive enzyme inhibitor is modified using a coupling agent, and then in step (2), the mesoporous silica or the digestive enzyme inhibitor is grafted via the coupling agent.

7. The preparation method according to claim 6, wherein In step A, the coupling agent is a silane coupling agent, and the amount of the silane coupling agent is 5 mol%-30 mol%.

8. The preparation method according to claim 7, wherein Before the silane coupling agent reacts with the digestive enzyme inhibitor, it first reacts with the linker polyethylene glycol, and then connects with the digestive enzyme inhibitor through the functional group on the linker polyethylene glycol.

9. A graft-modified mesoporous silica composition, characterized in that: The invention comprises the graft-modified mesoporous silica according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

10. The composition according to claim 9, wherein Also included are lipase inhibitors.

11. Use of the graft-modified mesoporous silica according to any one of claims 1 to 4 or the modified mesoporous silica composition according to any one of claims 9 to 10 in the preparation of a drug for regulating metabolism in patients with obesity or diabetes.

12. A drug for treating obesity or diabetes, characterized in that: A composition comprising the graft-modified mesoporous silica according to any one of claims 1 to 4 or the modified mesoporous silica according to any one of claims 9 to 10.

13. The therapeutic drug according to claim 12, characterized in that The dosage form of the therapeutic drug is liquid, tablet, caplet or capsule.

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