Composite cross-linking agent and hydrogel of polysaccharide or derivative thereof cross-linked by composite cross-linking agent

Abstract

The present invention relates to a composite cross-linking agent comprising (1) a cross-linking agent A that performs cross-linking by an esterification reaction, and (2) a cross-linking agent B that performs a reaction by an amidation reaction. The composite cross-linking agent is used for cross-linking polysaccharide or derivatives thereof. The cross-linked polysaccharide or the derivative thereof has good swelling property and mechanical property, and the water absorption rate is more than or equal to 30 times. The weight loss tablet has good biocompatibility, is non-irritant to digestive tract mucosa, can be well degraded in vivo, is high in safety, and can play an obvious weight loss role in animals and human beings after being taken.

Description

[0001] This application claims priority to the prior application filed on March 7, 2024, with application number 202410265919.7, entitled “A composite cross-linking agent and a hydrogel of polysaccharides or their derivatives cross-linked therewith,” the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of hydrogels, and specifically relates to a composite crosslinking agent and a hydrogel of polysaccharides or their derivatives crosslinked by the composite crosslinking agent. Background Art

[0003] Polymers formed by crosslinking polysaccharides or their derivatives are crosslinked hydrophilic polymers capable of absorbing and retaining large amounts of water. The crosslinks between the polymer chains form a network that ensures the structural integrity of the hydrogel, allowing the aqueous phase to be retained within the molecular grid, causing the hydrogel to swell a certain amount in volume and mass during this process. Prior applications, including CN201280036565.4 and CN201680011075.7, have successfully prepared water-absorbent polymer hydrogels by crosslinking water-soluble cellulose derivatives with polycarboxylic acids. This preparation method involves selecting an appropriate heat treatment temperature and time to form the crosslinked polymer. However, these polymer hydrogels are prepared solely through esterification crosslinking, resulting in insufficient crosslinking strength, unsatisfactory swelling properties and mechanical strength, and poor user experience. Swelling properties determine the volume expansion ratio, while mechanical properties determine stability and durability. Therefore, there is a need to develop new crosslinking agents that can significantly improve both the swelling and mechanical properties of polysaccharide hydrogels. Summary of the Invention

[0004] In order to solve the above technical problems, the present invention provides a composite crosslinking agent and a hydrogel of polysaccharide or its derivatives crosslinked therewith. The hydrogel of polysaccharide or its derivatives has good swelling and mechanical properties and a water absorption rate of ≥30 times.

[0005] Thus, in a first aspect, the present invention relates to a composite crosslinking agent comprising (1) a crosslinking agent A that crosslinks via an esterification reaction, and (2) a crosslinking agent B that reacts via an amidation reaction.

[0006] In one embodiment of the present invention, the crosslinking agent A for crosslinking by esterification is selected from a polycarboxylic acid or an anhydride thereof. The polycarboxylic acid comprises at least two carboxylic acid groups. For example, the polycarboxylic acid may be a dicarboxylic acid, a tricarboxylic acid, a tetracarboxylic acid or even a carboxylic acid of higher functionality. The polycarboxylic acid may be an aliphatic, alicyclic or aromatic polycarboxylic acid. The aliphatic polycarboxylic acid may be a C2-C 18 Aliphatic polycarboxylic acid, preferably C2-C 10Aliphatic polycarboxylic acids, which may be saturated or unsaturated, such as tartaric acid, malic acid, citric acid, oxalic acid, succinic acid, maleic acid, glutaric acid, adipic acid or butanetetracarboxylic acid. 18 Aliphatic polycarboxylic acid, preferably C6-C 10 Aliphatic polycarboxylic acids, such as cyclohexanedicarboxylic acid. Aromatic polycarboxylic acids can be C8-C 18 Aromatic polycarboxylic acid, preferably C8-C 12 Aromatic polycarboxylic acids, such as terephthalic acid, phthalic acid, isophthalic acid, pyromellitic acid, etc. Preferably, crosslinking agent A is selected from at least one of tartaric acid, malic acid, citric acid, oxalic acid, succinic acid, maleic acid, phthalic acid, isophthalic acid, terephthalic acid, glutaric acid, adipic acid, and butanetetracarboxylic acid. More preferably, crosslinking agent A is selected from at least one of tartaric acid, malic acid, citric acid, oxalic acid, and succinic acid. Most preferably, crosslinking agent A is citric acid.

[0007] In one embodiment of the present invention, the cross-linking agent B that reacts via an amidation reaction is selected from a compound containing an amino group. The number of amino groups may be 1, 2, 3, or more. When the number of amino groups is 1, the cross-linking agent B may also contain a carboxyl group. Cross-linking agents B containing one amino group may be selected from amino acids. Preferably, the amino acid is selected from at least one of glycine, alanine, glutamic acid, leucine, isoleucine, valine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine; more preferably, the amino acid is selected from at least one of alanine (which may be L-alanine or D-alanine), glutamic acid, isoleucine, leucine, valine, asparagine, and glutamine. Most preferably, the amino acid is alanine. Cross-linking agents B containing two, three, or more amino groups may be selected from aliphatic or aromatic diamines, triamines, or higher-functionality amines. Preferably, the crosslinking agent B containing 2, 3 or more amino groups can be selected from at least one of ethylenediamine, propylenediamine, butylenediamine, pentanediamine, hexamethylenediamine, heptamethylenediamine, octanediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine and the like.

[0008] In the composite crosslinking agent, the mass ratio of crosslinking agent A to crosslinking agent B may be 1:100 to 100:1, preferably 1:50 to 50:1, more preferably 1:10 to 10:1, and most preferably 1:10 to 5:1, for example 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1 or 4:1.

[0009] In a preferred embodiment of the present invention, the composite cross-linking agent comprises:

[0010] (1) a cross-linking agent A for cross-linking polysaccharides by esterification, which is selected from at least one of tartaric acid, malic acid, citric acid, oxalic acid and succinic acid;

[0011] (2) a cross-linking agent B for cross-linking polysaccharides by amidation reaction, which is selected from L-alanine, D-alanine, glutamic acid,

[0012] At least one of isoleucine, leucine, valine, asparagine and glutamine.

[0013] In a preferred embodiment of the present invention, the composite cross-linking agent is selected from a combination of citric acid and alanine (which may be L-alanine or D-alanine). In this combination, the mass ratio of citric acid to alanine may be 1:100 to 100:1, preferably 1:50 to 50:1, more preferably 1:10 to 10:1, and most preferably 1:10 to 5:1, for example, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, or 4:1.

[0014] The composite cross-linking agent of the present invention can be used for cross-linking polysaccharides or their derivatives.

[0015] In a second aspect, the present invention relates to a cross-linked polysaccharide or a derivative thereof, wherein the polysaccharide or the derivative thereof is cross-linked using the composite cross-linking agent of the present invention.

[0016] The polysaccharide or its derivative can be selected from cellulose or its derivative containing carboxyl or carboxyalkyl groups, alginic acid or its derivative, pectin or its derivative, heparin or its derivative, hyaluronic acid or its derivative, chondroitin or its derivative.

[0017] Cellulose derivatives include, but are not limited to, carboxylated cellulose or its salts, carboxyalkylated cellulose or its salts. The carboxylated cellulose or carboxyalkylated cellulose may also be optionally alkylated and hydroxyalkylated. Carboxyalkyl cellulose materials may be obtained by treating a cellulosic material with a carboxyalkylating agent, such as a chloroalkanoic acid, typically monochloroacetic acid, and a base, such as sodium hydroxide, optionally in the presence of an alcohol. The alkyl group may be C1-C 18 Alkyl, preferably C1-C 10 An alkyl group, more preferably a C1-C5 alkyl group. Examples of cellulose derivatives include, but are not limited to, carboxymethyl cellulose or its salts, carboxyethyl cellulose or its salts, and the like. The cellulose derivative is preferably carboxymethyl cellulose or its salts, such as sodium carboxymethyl cellulose. The salt may be an alkali metal salt, such as a lithium, sodium, or potassium salt; or an ammonium salt. Preferably, the salt is a pharmaceutically acceptable salt, such as a sodium salt or a potassium salt.

[0018] The alginic acid derivative may include alginate. The salt may be an alkali metal salt, such as a lithium, sodium or potassium salt; or an ammonium salt. Preferably, the salt is a pharmaceutically acceptable salt, such as a sodium salt or a potassium salt.

[0019] Examples of pectin derivatives include salts of pectin, or amidated pectin or its salts. The salts may be alkali metal salts, such as lithium, sodium, or potassium salts, or ammonium salts. Preferably, the salts are pharmaceutically acceptable salts, such as sodium or potassium salts.

[0020] Examples of heparin derivatives include heparin or a salt thereof, heparan sulfate or a salt thereof. The salt may be an alkali metal salt, such as a lithium, sodium, or potassium salt; or an ammonium salt. Preferably, the salt is a pharmaceutically acceptable salt, such as a sodium salt or a potassium salt.

[0021] Examples of hyaluronic acid derivatives include salts of hyaluronic acid, oxidized hyaluronic acid, or salts of oxidized hyaluronic acid. The salt may be an alkali metal salt, such as a lithium, sodium, or potassium salt; or an ammonium salt. Preferably, the salt is a pharmaceutically acceptable salt, such as a sodium salt or a potassium salt.

[0022] Examples of chondroitin derivatives include salts of chondroitin, chondroitin sulfate, or salts thereof. The salts may be alkali metal salts, such as lithium, sodium, or potassium salts; or ammonium salts. Preferably, the salts are pharmaceutically acceptable salts, such as sodium or potassium salts.

[0023] Preferably, the weight average molecular weight of the polysaccharide is between 20,000 and 2,000,000, preferably between 50,000 and 1,000,000, for example, 50,000, 100,000, 150,000, 200,000, 250,000, 300,000, 350,000, 400,000, 450,000, 500,000, 550,000, 600,000, 650,000, 700,000, 750,000, 800,000, 850,000, 900,000, 950,000 or 1,000,000.

[0024] Preferably, the viscosity of the polysaccharide in a 1 wt % aqueous solution at 25° C. is 100-8000 CP, preferably 400-5000 CP, for example 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900 or 5000 CP. The viscosity is measured using a rotational viscometer.

[0025] Preferably, the degree of substitution of the polysaccharide may be 0-1.0, for example, 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0.

[0026] The amount of the composite cross-linking agent used may be 0.01-15% by weight of the polysaccharide, preferably 0.1-10% by weight, and more preferably 0.2-6% by weight.

[0027] In a preferred embodiment of the present invention, the cross-linked polysaccharide or its derivative is sodium carboxymethyl cellulose, and the composite cross-linking agent is alanine and citric acid.

[0028] In a third aspect, the present invention provides a method for preparing a cross-linked polysaccharide or a derivative thereof, comprising reacting the polysaccharide or the derivative thereof with the composite cross-linking agent.

[0029] In one embodiment of the present invention, the cross-linking reaction may be carried out at 60-150° C., preferably 70-100° C. The reaction time may be 4-72 h, preferably 10-60 h.

[0030] The cross-linking reaction can be carried out without using a catalyst.

[0031] In one embodiment of the present invention, the method comprises mixing crosslinking agent A, crosslinking agent B, and a polysaccharide or a derivative thereof, and then subjecting them to a crosslinking reaction. Preferably, crosslinking agent A, crosslinking agent B, and a polysaccharide or a derivative thereof are added to water (e.g., deionized water), mixed, and then subjecting them to a crosslinking reaction.

[0032] More preferably, the method may comprise the following steps:

[0033] 1) dissolving crosslinking agents A and B in water to obtain solution 1;

[0034] 2) dispersing the polysaccharide or its derivative in water to obtain dispersion 2;

[0035] 3) Mixing solution 1 and dispersion 2,

[0036] 4) drying and dehydrating the mixture obtained in step 3) and simultaneously performing a cross-linking reaction.

[0037] Step 1) can be carried out at a temperature between room temperature and 80°C, preferably between room temperature and 60°C. Step 1) can be carried out with stirring, for example, using a magnetic stirrer. The stirring rate can be 10-5000 rpm, preferably 30-1000 rpm, and more preferably 40-200 rpm. The stirring time is not limited, as long as crosslinker A and crosslinker B are completely dissolved, and can be, for example, 10 minutes to 5 hours, such as 30 minutes to 2 hours.

[0038] Step 2) can be carried out at a temperature between room temperature and 80° C., preferably between room temperature and 60° C. Step 2) can be carried out under stirring at a stirring rate of 10-5000 rpm, preferably 30-1000 rpm, and more preferably 40-200 rpm. The stirring time can be from 10 minutes to 6 hours, preferably from 30 minutes to 4 hours.

[0039] Step 3) can be performed by adding solution 1 to dispersion 2. After the addition is completed, the resulting mixture can be stirred at a temperature ranging from room temperature to 80° C., preferably 30-60° C. The stirring time is not limited, as long as the polysaccharide or its derivative is completely dissolved, for example, 10 minutes to 6 hours, preferably 30 minutes to 4 hours.

[0040] Step 4) may include drying and dehydrating the resulting mixture of the polysaccharide or its derivative and the crosslinking agent under vacuum conditions while simultaneously carrying out a crosslinking reaction. The vacuum degree may be between -0.05 MPa and -0.1 MPa, preferably between -0.07 MPa and -0.1 MPa. The drying and crosslinking temperature may be between 30°C and 100°C, preferably between 60°C and 90°C. The drying and crosslinking time may be between 1 and 70 hours, preferably between 5 and 60 hours. The moisture content of the product may be less than 10%.

[0041] In another aspect, the present invention provides a hydrogel comprising the cross-linked polysaccharide or its derivative. The hydrogel is formed by the cross-linked polysaccharide or its derivative absorbing a certain amount of water, wherein the water is stored in the cross-linked network structure formed by the cross-linked polysaccharide or its derivative, and the water absorption rate is ≥30 times.

[0042] The cross-linked polysaccharide or its derivative or hydrogel can be used as medicine, pharmaceutical excipient, medical device, food, food additive, dietary supplement, health product, meal replacement, dietary supplement, etc.

[0043] In another aspect, a composition comprising the cross-linked polysaccharide or its derivative or the hydrogel is provided. The composition may further include excipients. The composition may further include additives such as preservatives, solubilizers / surfactants, buffers, isotonicity regulators, suspending agents, dispersants, wetting agents, etc.

[0044] The composition of the present invention can be prepared into the forms of common tablets, capsules, powders, granules, syrups, gels, suspensions, dispersible tablets, chewable tablets, effervescent tablets, capsules, granules, sustained-release preparations and the like.

[0045] The composition can be used to prevent and treat diseases related to overweight, including but not limited to overweight, obesity, prediabetes, diabetes, high blood cholesterol, hypertension, cardiovascular and cerebrovascular diseases, constipation, osteoarthritis, gout, sleep apnea syndrome, infertility, menstrual disorders, abnormal ovulation, abnormal hormone levels, etc.; it can also be used for health management and diet control, including weight loss, weight management, reducing calorie intake, reducing appetite, promoting satiety, etc.

[0046] Therefore, in another aspect, the present invention relates to use of the composition in the preparation of a medicament for preventing and treating diseases associated with excess weight or for health management and diet control.

[0047] The use includes taking it 10-60 minutes before a meal (such as 10, 20, 30, 40, 50, 60 minutes before a meal), preferably taking it between 30-60 minutes before a meal (such as 30, 40, 50, 60 minutes before a meal).

[0048] The composition can be taken once a day, twice a day, three times a day or more times a day. Preferably, the composition can be taken three times a day. Most preferably, the composition can be taken 30 minutes to 60 minutes before three meals a day.

[0049] A suitable dosage may comprise a predetermined amount of the cross-linked polysaccharide or its derivative or the hydrogel calculated to produce a desired therapeutic effect. A person skilled in the art may determine a suitable dosage based on patient characteristics well known in the art, such as age, weight, sex, condition, complications, other diseases, etc.

[0050] Beneficial effects:

[0051] By cross-linking the cross-linked polysaccharides or their derivatives through the composite cross-linking agent of the present invention, a more stable three-dimensional rigid network structure can be formed compared to polymers or hydrogels cross-linked only by esterification reaction, which has stronger swelling properties and greatly enhanced mechanical strength / elastic modulus. Compared with previously known hydrogels, it has obvious performance advantages in mechanical strength and medium uptake rate.

[0052] The present invention uses a composite cross-linking agent without using a catalyst, thereby eliminating the problem of low yield due to the presence of residual catalyst or the need to remove the residual catalyst.

[0053] The cross-linked polymer or its derivative or hydrogel of the present invention has good biocompatibility, is non-irritating to the digestive tract mucosa, can be well degraded in the body, is highly safe, and can significantly reduce weight in both animals and humans after administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1The curves of gastric mass changes after taking different samples are shown;

[0055] Figure 2 The gastric emptying curve of the sample after a meal is shown;

[0056] Figure 3 Shown are images of the appearance of pyloric discharge from an in vitro simulated test.

[0057] Figure 4 The in vitro dynamic human gastrointestinal simulated digestive system used in the examples is shown. DETAILED DESCRIPTION

[0058] Example 1:

[0059] Material formula:

[0060]

[0061]

[0062] Preparation steps:

[0063] 1. Dissolve 0.2 g alanine and 0.05 g anhydrous citric acid in 20 ml of deionized water and stir with a magnetic stirrer until completely dissolved to obtain solution A.

[0064] 2. Add 4.75 g of CMC-Na to a flask containing 150 ml of deionized water. Stir at 60 rpm for 2 h, then add solution A. Continue stirring in a 40°C oil bath for 1 h.

[0065] 3. After being completely dissolved, the sample was placed in an oven at a temperature of 80°C and a vacuum degree of -0.08 MPa for 50 hours and then taken out to obtain the final polymer.

[0066] The structural diagram of the polymer of Example 1 is as follows:

[0067]

[0068] Control group 1:

[0069] Material formula:

[0070] Serial number raw materials Molecular weight 1 Sodium carboxymethyl cellulose (CMC-Na, degree of substitution 0.9) Mw=250KDa 2 Citric acid (CA) /

[0071] Preparation steps:

[0072] 1. Dissolve 0.2 g of citric acid in 20 ml of deionized water and stir with a magnetic stirrer until completely dissolved to obtain Solution A.

[0073] 2. Add 4.8 g of CMC-Na to a flask containing 150 ml of deionized water, stir at 60 rpm for 2 h, then add solution A and continue stirring in a constant temperature oil bath at 40 °C for 1 h.

[0074] 3. After being completely dissolved, the sample was placed in an oven at a temperature of 80°C and a vacuum degree of -0.08 MPa for 50 hours and then taken out to obtain the final polymer.

[0075] Performance testing:

[0076] 1. Water absorption

[0077] The water absorption of the samples prepared in Example 1 and Control Group 1 was measured by the following method:

[0078] a) Standard simulated gastric fluid (SGF) was prepared by dissolving 7 mL of 37% HCl, 2 g of NaCl, and 3.2 g of pepsin in deionized water to 1000 mL. Diluted SGF (Di-SGF) was prepared by mixing 1 part of SGF with 8 parts of deionized water.

[0079] b) Take a 150ml empty beaker #1 and weigh its mass (W1);

[0080] c) Place 100g of the Di-SGF prepared in step b) into another 150ml beaker, Beaker #2. Using weighing paper, accurately weigh 0.5g of the sample; add this sample to Beaker #2 and gently stir with a magnetic stirrer for 30 minutes without creating a vortex to obtain a mixture of hydrogel and water. Filter free water using a 75-mesh sieve and drain the hydrogel for 10 ± 1 minutes. Transfer the drained hydrogel to Beaker #1 and weigh it (W2). The resulting drained material is the hydrogel.

[0081] The water absorption rate is calculated according to the following formula:

[0082] Water absorption rate = (W2-W1) / 0.5.

[0083] The assay was performed in triplicate and the results were averaged.

[0084] 2. Residual rate in simulated gastric volume in vitro

[0085] (1) Injection: single dose of 3 capsules (the hydrogel particles of Example 1 and Control Group 1 were respectively packed into capsules, with a content of 0.75 g / capsule) + 450 mL of water + 250 g of food;

[0086] (2) Dissolution medium: simulated gastric fluid (formula of the 2010 Chinese Pharmacopoeia);

[0087] (3) Test method: continuous experiment (n = 1);

[0088] (4) Test equipment: An in vitro dynamic human gastrointestinal simulated digestive system was used to conduct dynamic in vitro studies under fasting and feeding conditions. The test mainly focused on gastric digestion and did not involve intestinal digestion. The in vitro dynamic human gastrointestinal simulated digestive system was produced by Xiaodong Yijian (Suzhou) Instrument Equipment Co., Ltd. The specific structure of the in vitro dynamic human gastrointestinal simulated digestive system is shown in Figure 4 , where the left picture is the overall structure of the system, and the right picture is an enlarged view of the upper structure of the system.

[0089] The performance test results of Example 1 and Control Group 1 are shown in the following table:

[0090] Table 1

[0091] Serial number Example 1 Control group 1 Water absorption rate 119 80 Residual rate of simulated gastric volume in vitro after 4 hours 51.72％ 12.25％

[0092] As shown in Table 1, Example 1 has a water absorption rate of 119, which is significantly better than the water absorption rate of 80 in Control 1. Furthermore, the Example and Control samples were subjected to a simulated gastric emptying test using an in vitro dynamic human gastrointestinal simulated digestive system. The residual gastric volume of Example 1 after 4 hours was 51.72%, far superior to that of Control 1 (12.25%). Example 1 has excellent gastric emptying delaying properties.

[0093] The appearance pictures of pyloric discharge from the in vitro simulation test of Example 1 and Control Group 1 are as follows: Figure 3 As shown. Figure 3 It can be seen that the color of the pyloric orifice discharge of Example 1 after eating (eating started 30 minutes ago) (food is yellow after eating, and the sample is colorless) is significantly lighter than that of Control Group 1, indicating that the amount discharged by Example 1 is small, and it has a better effect of delaying gastric emptying.

[0094] The polymer of Example 1 was subjected to in vitro cytotoxicity testing according to GB / T 16886.5-2017, demonstrating no potential toxic effects on L-929 cells. It was also non-irritating to the digestive tract mucosa. In vitro degradation tests in simulated colonic fluid demonstrated that the product degraded in 48 hours following dehydration. This demonstrated excellent biocompatibility, robust in vivo degradation, high safety, and non-toxicity, demonstrating significant weight loss in both animals and humans.

[0095] The above is an exemplary description of the embodiments of the present invention. However, the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A composite crosslinking agent comprising (1) a crosslinking agent A that crosslinks by an esterification reaction, and (2) a crosslinking agent B that reacts by an amidation reaction.

2. The composite crosslinking agent according to claim 1, wherein the crosslinking agent A is selected from polycarboxylic acids or their anhydrides; Preferably, the polycarboxylic acid may be a dibasic acid, a tribasic acid, a tetrabasic acid or even a carboxylic acid of higher functionality; More preferably, the polycarboxylic acid may be an aliphatic, alicyclic or aromatic polycarboxylic acid; More preferably, the aliphatic polycarboxylic acid may be C2-C 18 Aliphatic polycarboxylic acid, preferably C2-C 10 aliphatic polycarboxylic acids, which may be saturated or unsaturated, for example tartaric acid, malic acid, citric acid, oxalic acid, succinic acid, maleic acid, glutaric acid, adipic acid or butanetetracarboxylic acid; More preferably, the alicyclic polycarboxylic acid may be C6-C 18 Aliphatic polycarboxylic acid, preferably C6-C 10 Aliphatic polycarboxylic acids, such as cyclohexanedicarboxylic acid; More preferably, the aromatic polycarboxylic acid may be C8-C 18 Aromatic polycarboxylic acid, preferably C8-C 12 Aromatic polycarboxylic acids, such as terephthalic acid, phthalic acid, isophthalic acid, pyromellitic acid, etc. Most preferably, crosslinking agent A is selected from at least one of tartaric acid, malic acid, citric acid, oxalic acid, succinic acid, maleic acid, phthalic acid, isophthalic acid, terephthalic acid, glutaric acid, adipic acid, and butanetetracarboxylic acid. More preferably, crosslinking agent A is selected from at least one of tartaric acid, malic acid, citric acid, oxalic acid, and succinic acid. Most preferably, crosslinking agent A is citric acid. wherein the crosslinking agent B is selected from compounds containing an amino group; Preferably, the number of amino groups is 1, 2, 3 or more; More preferably, when the number of amino groups is 1, the crosslinking agent B further comprises a carboxyl group; More preferably, the cross-linking agent B containing one amino group is selected from amino acids. Preferably, the amino acid is selected from at least one of glycine, alanine, glutamic acid, leucine, isoleucine, valine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine; more preferably, the amino acid is selected from at least one of alanine, glutamic acid, isoleucine, leucine, valine, asparagine, and glutamine. Most preferably, the amino acid is alanine. Preferably, the crosslinking agent B containing 2, 3 or more amino groups is selected from aliphatic, aromatic diamines, triamines or higher-functionality amines. Preferably, the crosslinking agent B containing 2, 3 or more amino groups can be selected from at least one of ethylenediamine, propylenediamine, butylenediamine, pentanediamine, hexamethylenediamine, heptamethylenediamine, octanediamine, diethylenetriamine, triethylenetetramine and tetraethylenepentamine.

3. The composite crosslinking agent according to claim 1 or 2, wherein the mass ratio of crosslinking agent A to crosslinking agent B is 1:100 to 100:1, preferably 1:50 to 50:1, more preferably 1:10 to 10:1, and most preferably 1:10 to 5:

1.

4. The composite cross-linking agent according to any one of claims 1 to 3, which is composed of: (1) a cross-linking agent A for cross-linking polysaccharides by esterification, which is selected from at least one of tartaric acid, malic acid, citric acid, oxalic acid and succinic acid; (2) A cross-linking agent B for cross-linking polysaccharides by amidation reaction, which is at least one selected from alanine, glutamic acid, isoleucine, leucine, valine, asparagine and glutamine.

5. A cross-linked polysaccharide or a derivative thereof, wherein the polysaccharide or the derivative thereof is cross-linked using the composite cross-linking agent according to any one of claims 1 to 4.

6. The cross-linked polysaccharide or its derivative according to claim 5, wherein the polysaccharide or its derivative is selected from cellulose or its derivative containing carboxyl or carboxyalkyl groups, alginic acid or its derivative, pectin or its derivative, heparin or its derivative, hyaluronic acid or its derivative, chondroitin or its derivative; Preferably, the cellulose derivative is selected from carboxylated cellulose or its salt, carboxyalkylated cellulose or its salt; Preferably, the alginic acid derivative is selected from alginate; Preferably, the pectin derivative is selected from a salt of pectin, or amidated pectin or its salt; Preferably, the heparin derivative is selected from heparin or its salt, heparan sulfate or its salt; Preferably, the hyaluronic acid derivative is selected from a salt of hyaluronic acid, oxidized hyaluronic acid or a salt of oxidized hyaluronic acid; Preferably, the chondroitin derivative is selected from chondroitin salts, chondroitin sulfate or salts thereof.

7. A method for preparing the cross-linked polysaccharide or its derivative according to claim 5 or 6, comprising reacting the polysaccharide or its derivative with a composite cross-linking agent. A hydrogel comprising the cross-linked polysaccharide or a derivative thereof according to claim 5 or 6.

9. A composition comprising the cross-linked polysaccharide or derivative thereof according to claim 5 or 6 or the hydrogel according to claim 8.

10. Use of the cross-linked polysaccharide or derivative thereof according to claim 5 or 6, the hydrogel according to claim 8, or the composition according to claim 9 in the preparation of a medicament for preventing and treating diseases associated with overweight or for health management and diet control.

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