A hydrogel for repairing intestinal barrier and application thereof in preparation of a drug for treating inflammatory bowel disease

Abstract

The application provides a hydrogel for repairing intestinal barrier and application thereof in preparation of a drug for treating inflammatory bowel disease, and belongs to the technical field of biomedical materials. The hydrogel comprises a ternary polysaccharide matrix, a composite buffer cross-linking component, a layered functional component and a flora regulation micro-particle. The ternary polysaccharide matrix is composed of sodium alginate, carboxymethyl chitosan and modified konjac glucomannan. The composite buffer cross-linking component is a combination of calcium chloride and sodium citrate. The layered functional component comprises an antioxidant functional component embedded in the inner layer and a mucosa repair functional component covalently grafted on the outer layer. The flora regulation micro-particle is a fermented astragalus polysaccharide micro-particle embedded in the ternary polysaccharide matrix. The application can effectively improve the structural stability of the hydrogel, realize layered repair, and simultaneously regulate the intestinal micro-ecology, thereby significantly improving the comprehensive repair performance of the intestinal barrier and solving the technical problems of poor structural stability of the existing hydrogel, limited repair function and lack of flora regulation capacity.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to a hydrogel for repairing the intestinal barrier and its application in the preparation of drugs for treating inflammatory bowel disease. Background Technology

[0002] Inflammatory bowel disease (IBD) is characterized by intestinal mucosal damage, intestinal barrier structure impairment, and intestinal microecological dysbiosis. It has a high clinical incidence and recurrence rate, severely impacting patients' digestive and immune functions. Hydrogels, due to their good biocompatibility and ability to adhere to mucosal wounds, are widely used in intestinal barrier repair and as an adjunct therapy for intestinal inflammation. Currently, most commercially available and researched intestinal repair hydrogels utilize conventional single or binary polysaccharide substrates combined with pure metal ions for cross-linking. Functional components are generally loaded using a homogeneous, mixed approach, achieving only basic wound coverage and basic anti-inflammatory effects.

[0003] However, existing traditional intestinal repair hydrogels struggle to achieve efficient and long-lasting intestinal barrier repair. Firstly, traditional hydrogels utilize only single or binary polysaccharide substrates, resulting in weak overall matrix structure and poor cross-linking performance. Combined with a pure calcium ion cross-linking mode without buffering regulation, the cross-linking rate is difficult to control. The resulting hydrogels exhibit disordered pore arrangement and poor mechanical uniformity, making them prone to breakage and detachment in the complex environment of gastrointestinal dynamics, and insufficient effective retention time at the lesion site. Secondly, existing hydrogels are all homogeneous monolithic structures, unable to adapt to the layered repair needs of inner layer anti-oxidative damage and outer layer mucosal repair promotion. The repair pathways are relatively limited, and targeted repair is insufficient. Finally, conventional repair hydrogels only possess basic anti-inflammatory and mucosal healing effects, failing to address the intestinal flora imbalance commonly associated with inflammatory bowel disease. They can only repair the physical intestinal barrier, unable to simultaneously repair the microecological barrier, ultimately leading to incomplete wound healing and frequent recurrence of the condition.

[0004] Therefore, developing an intestinal repair hydrogel with a multi-component composite matrix, controllable cross-linking structure, layered functional loading, and microbial regulation function is an urgent need in this field. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, the purpose of this invention is to provide a hydrogel for repairing the intestinal barrier and its application in the preparation of drugs for treating inflammatory bowel disease. This hydrogel can effectively improve the structural stability of the hydrogel, achieve layered repair, and simultaneously regulate the intestinal microecology, significantly improving the comprehensive repair performance of the intestinal barrier. This solves the technical problems of poor structural stability, limited repair function, and lack of microbial regulation ability of existing hydrogels.

[0006] To achieve the above objectives, the present invention provides the following solution: On the one hand, the present invention provides a hydrogel for repairing the intestinal barrier, comprising a ternary polysaccharide matrix, a composite buffer crosslinking component, a layered loaded functional component, and microbial regulation microparticles; The ternary polysaccharide matrix is ​​composed of sodium alginate, carboxymethyl chitosan, and modified konjac glucomannan; The composite buffer crosslinking component is a combination of calcium chloride and sodium citrate; The layered loading functional components include an inner layer of embedded antioxidant functional components and an outer layer of covalently grafted mucosal repair functional components. The microbial community regulating microparticles are fermented Astragalus polysaccharide microparticles embedded in the ternary polysaccharide matrix; The content of each raw material component by weight is as follows: sodium alginate 45-55 parts, carboxymethyl chitosan 25-35 parts, modified konjac glucomannan 15-25 parts, antioxidant functional component 4-8 parts, mucosal repair functional component 3-5 parts, fermented astragalus polysaccharide microparticles 6-10 parts, calcium chloride 1.0-1.4 parts, sodium citrate 0.6-1.0 parts, and purified water 750-850 parts.

[0007] Preferably, the antioxidant functional component is reduced glutathione, and the mucosal repair functional component is casein phosphopeptide.

[0008] Preferably, the particle size of the fermented astragalus polysaccharide microparticles is 150~350nm.

[0009] On the other hand, the present invention also provides a method for preparing the above-mentioned hydrogel, comprising the following steps: S1. Heat purified water under stirring, add sodium alginate, carboxymethyl chitosan and modified konjac glucomannan in sequence, and continue stirring until all raw materials are completely dissolved to obtain a homogeneous and transparent colloidal mother liquor. S2. After ultrasonic dispersion pretreatment, fermented Astragalus polysaccharide microparticles are added to colloidal mother liquor and stirred continuously to make the microparticles uniformly dispersed in the colloid, thus obtaining a mixed colloid with uniform components. S3. Prepare a calcium chloride and sodium citrate composite crosslinking solution and add it dropwise into the mixed colloid at a uniform rate. The crosslinking is completed by standing to obtain a basic hydrogel with a complete structure. S4. The prepared basic hydrogel was subjected to inner layer antioxidant functional component embedding treatment and outer layer mucosal repair functional component covalent grafting treatment to form a functional load structure with inner and outer layers. S5. The hydrogel that has undergone layered functional modification is rinsed, drained, and cut into shape to obtain the final hydrogel product.

[0010] Preferably, in step S1, the water temperature is controlled at 40~50℃, the stirring speed is 250~350r / min, and the stirring is continued for 35~45min.

[0011] Preferably, in step S2, when pretreating the fermented astragalus polysaccharide microparticles, ultrasonic dispersion at 100-150W power is performed for 3-8 minutes, followed by stirring in colloidal mother liquor at 120-180r / min for 12-18 minutes.

[0012] Preferably, in step S3, a calcium chloride-sodium citrate composite crosslinking solution with a mass fraction of 0.15%~0.25% is prepared and added dropwise at a rate of 0.8~1.2 mL / min, and allowed to stand for crosslinking at room temperature for 20~30 min, wherein the mass ratio of calcium chloride to sodium citrate in the composite crosslinking solution is 1.0~1.4:0.6~1.0.

[0013] Preferably, in step S4, the base hydrogel is placed in an aqueous solution of reduced glutathione with a concentration of 0.4~0.6 mg / mL and soaked at 3~5℃ for 10~14 h to complete the inner layer embedding; then the hydrogel with the inner layer embedded is placed in a phosphate buffer solution with a pH of 7.2~7.6 containing 0.2~0.4 mg / mL casein phosphopeptide and shaken at 23~27℃ and 100~140 r / min for 7~9 h, so that the mucosal repair functional components are covalently grafted and fixed on the outer surface of the hydrogel, thus completing the layered functional modification of the hydrogel.

[0014] Furthermore, the hydrogel described above can be used in the preparation of drugs for treating inflammatory bowel disease, wherein the dosage form of the drug is oral gel granules or rectal gel suppositories.

[0015] Compared with the prior art, the present invention discloses at least the following technical effects: First, this invention employs a ternary polysaccharide matrix composed of sodium alginate, carboxymethyl chitosan, and modified konjac glucomannan, combined with a composite crosslinking component of calcium chloride and sodium citrate. Utilizing the differentiated structural characteristics of the three polysaccharide molecular chains, an interpenetrating and complementary composite network is formed. Simultaneously, the buffering and complexing effect of sodium citrate regulates the calcium ion crosslinking rate, solving the technical problems of uneven gel formation, disordered pores, and weak mechanical properties caused by the instantaneous crosslinking of single calcium ions with traditional mono- and binary polysaccharide substrates. Therefore, this invention can form a three-dimensional crosslinking network with uniform pore size, excellent pore connectivity, and a dense and stable structure, significantly optimizing the overall mechanical properties and structural uniformity of the hydrogel. This effectively enhances the hydrogel's resistance to breakage and detachment under complex environments of dynamic peristalsis and fluid erosion in the gastrointestinal tract, greatly extending the effective retention time of the hydrogel at intestinal lesions. This lays a solid structural foundation for the continuous and stable repair and anti-inflammatory effects, solving the technical problems of poor stability and insufficient lesion retention in traditional hydrogels.

[0016] Secondly, this invention provides a differentiated layered loading structure with an inner layer containing embedded antioxidant functional components and an outer layer covalently grafted with mucosal repair functional components, abandoning the traditional single-mode approach of homogeneous mixing and simultaneous release of all functional components in hydrogels. The inner-layer embedded antioxidant components can stably remain within the hydrogel, continuously clearing intestinal oxidative stress products, inhibiting local inflammatory proliferation, and blocking persistent damage to the intestinal barrier. The outer-layer covalently grafted mucosal repair components are firmly bound and can continuously act on the intestinal lesion, targeting and inducing the proliferation and migration of intestinal epithelial cells, accelerating the healing of damaged mucosa and the reconstruction of the intestinal barrier structure. Through this synergistic repair mechanism of inner and outer layers with each component performing its specific function, it precisely adapts to the multi-level pathological characteristics of oxidative damage and mucosal defects in intestinal lesions of inflammatory bowel disease, effectively improving the repair precision and integrity of intestinal barrier damage, and solving the technical problems of poor targeting, single repair level, and limited effectiveness of traditional hydrogels.

[0017] Third, this invention uniformly embeds fermented astragalus polysaccharide microparticles within a ternary polysaccharide matrix. These microparticles do not participate in cross-linking reactions, allowing them to remain stably in the hydrogel system for a long period and continuously release active ingredients. This overcomes the limitations of traditional intestinal repair hydrogels, which can only repair the physical mucosal barrier and lack microecological regulation functions. The embedded fermented astragalus polysaccharide microparticles possess excellent intestinal flora regulation activity, effectively adjusting the structural ratio of beneficial and harmful bacteria in the gut, improving the imbalance of intestinal flora under inflammatory conditions, and repairing the intestinal microecological barrier. Therefore, this invention achieves dual synergistic repair of the intestinal physical barrier and microecological barrier, improving the intestinal inflammatory state from the root causes of pathological structure and microenvironment. This effectively avoids the problems of incomplete wound repair and recurrent inflammation caused by traditional single-repair methods, and to a certain extent improves the long-term effectiveness and stability of intestinal barrier repair. Detailed Implementation

[0018] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] It should be noted that, unless otherwise specified, the raw materials, reagents, instruments and equipment used in the embodiments, comparative examples and application tests of this invention are all commercially available biomedical grade conventional materials and equipment, and the preparation, reaction, modification and molding processes involved are all conventional standard operations in the field and can be completely reproduced.

[0020] Example 1 This embodiment aims to provide a structurally stable intestinal barrier repair hydrogel with antioxidant, anti-inflammatory, and preliminary microbial regulation capabilities. The raw materials are prepared according to the following mass ratio: 45 parts sodium alginate, 25 parts carboxymethyl chitosan, 15 parts modified konjac glucomannan, 4 parts reduced glutathione, 3 parts casein phosphopeptide, 6 parts fermented astragalus polysaccharide microparticles, 1.0 part calcium chloride, 0.6 parts sodium citrate, and 750 parts purified water. The particle size of the fermented astragalus polysaccharide microparticles is controlled to be 150 nm.

[0021] Based on the raw material composition provided above, the specific preparation process of the hydrogel in this embodiment is as follows: First, the polysaccharide matrix solution was prepared by heating a quantitative amount of purified water to 40°C and stirring at a constant speed of 250 r / min for 35 min. Then, sodium alginate, carboxymethyl chitosan, and modified konjac glucomannan were added in sequence and stirred until all the powders were completely dissolved to form a uniform, transparent colloidal mother liquor without agglomerates, which ensures the uniform formation of the subsequent three-dimensional network structure.

[0022] Subsequently, functional microparticle dispersion pretreatment was carried out. The quantitative fermented Astragalus polysaccharide microparticles were ultrasonically dispersed at 100W power for 3 minutes to break the microparticle aggregation. The dispersed microparticle system was then added to the above colloidal mother liquor, and the stirring speed was adjusted to 120r / min and stirred continuously for 12 minutes to make the microparticles uniformly dispersed in the colloidal system, thus obtaining a homogeneous mixed colloid.

[0023] Subsequently, a buffered composite crosslinking molding process was carried out. A composite buffer crosslinking solution with a mass fraction of 0.15% and a mass ratio of calcium chloride to sodium citrate of 1.0:0.6 was prepared and added to the mixed colloid at a low and uniform rate of 0.8 mL / min to avoid structural defects caused by instantaneous crosslinking. The mixture was allowed to stand at room temperature for 20 min for crosslinking to obtain a basic hydrogel with a dense structure and uniform pores.

[0024] Further functional modification of the inner and outer layers was carried out. The prepared base hydrogel was placed in a 0.4 mg / mL reduced glutathione aqueous solution and soaked at 5°C for 10 h to complete the uniform embedding of the inner layer antioxidant functional components, thereby realizing the long-term antioxidant and oxidative stress damage blocking function of the inner layer of the hydrogel. Subsequently, the modified inner layer hydrogel was transferred to a phosphate buffer solution with a pH of 7.2 containing 0.2 mg / mL casein phosphopeptide and reacted continuously at 23°C and 100 r / min for 7 h to stably covalently graft casein phosphopeptide onto the outer layer of the hydrogel, giving the outer layer of the hydrogel the properties of targeted adhesion and promoting the healing of intestinal mucosal wounds.

[0025] Finally, the modified composite functional hydrogel was rinsed multiple times with sterile pure water to remove residual impurities on the surface, drained at a constant temperature to remove excess water, and cut and shaped according to medical standards to obtain the final intestinal repair hydrogel product.

[0026] Example 2 The difference between this embodiment and Embodiment 1 is that the raw material composition of this embodiment is 48 parts sodium alginate, 28 parts carboxymethyl chitosan, 18 parts modified konjac glucomannan, 5 parts reduced glutathione, 3.5 parts casein phosphopeptide, 7 parts fermented astragalus polysaccharide microparticles, 1.1 parts calcium chloride, 0.7 parts sodium citrate, and 780 parts purified water, and the particle size of the fermented astragalus polysaccharide microparticles is controlled to be 200 nm.

[0027] Based on the raw material composition provided above, the hydrogel preparation process in this embodiment is as follows: First, the polysaccharide matrix solution was prepared by heating a quantitative amount of purified water to 42°C and stirring at a constant speed of 280 r / min for 38 min. Then, sodium alginate, carboxymethyl chitosan, and modified konjac glucomannan were added in sequence and stirred until all the powders were completely dissolved to form a uniform, transparent colloidal mother liquor without agglomerates, which ensures the uniform formation of the subsequent three-dimensional network structure.

[0028] Subsequently, functional microparticle dispersion pretreatment was carried out. The quantitative fermented Astragalus polysaccharide microparticles were ultrasonically dispersed at 110W for 4 minutes to break the microparticle aggregation. The dispersed microparticle system was then added to the above colloidal mother liquor, and the stirring speed was adjusted to 140r / min and stirred continuously for 14 minutes to make the microparticles uniformly dispersed in the colloidal system, thus obtaining a homogeneous mixed colloid.

[0029] Subsequently, a buffered composite crosslinking molding process was carried out. A composite buffer crosslinking solution with a mass fraction of 0.18% and a mass ratio of calcium chloride to sodium citrate of 1.1:0.7 was prepared and added to the mixed colloid at a low and uniform rate of 0.9 mL / min to avoid structural defects caused by instantaneous crosslinking. The mixture was allowed to stand at room temperature for 22 min for crosslinking to obtain a basic hydrogel with a dense structure and uniform pores.

[0030] Further functional modification of the inner and outer layers was carried out. The prepared base hydrogel was placed in a 0.45 mg / mL reduced glutathione aqueous solution and soaked at 4°C for 11 h to complete the uniform embedding of the inner layer antioxidant functional components, thereby achieving the function of long-term antioxidant and blocking oxidative stress damage in the inner layer of the hydrogel. Subsequently, the modified inner layer hydrogel was transferred to a phosphate buffer solution with a pH of 7.2 containing 0.25 mg / mL casein phosphopeptide and reacted continuously at 24°C and 110 r / min for 7.5 h to stably covalently graft casein phosphopeptide onto the outer layer of the hydrogel, giving the outer layer of the hydrogel the properties of targeted adhesion and promoting the healing of intestinal mucosal wounds.

[0031] Finally, the modified composite functional hydrogel was rinsed multiple times with sterile pure water to remove residual impurities on the surface, drained at a constant temperature to remove excess water, and cut and shaped according to medical standards to obtain the final intestinal repair hydrogel product.

[0032] Example 3 The difference between this embodiment and Embodiment 1 is that, by weight, the raw materials in this embodiment are 50 parts sodium alginate, 30 parts carboxymethyl chitosan, 20 parts modified konjac glucomannan, 6 parts reduced glutathione, 4 parts casein phosphopeptide, 8 parts fermented astragalus polysaccharide microparticles, 1.2 parts calcium chloride, 0.8 parts sodium citrate, and 800 parts purified water, and the particle size of the fermented astragalus polysaccharide microparticles is controlled to be 250 nm.

[0033] Based on the raw material composition provided above, the hydrogel preparation process in this embodiment is as follows: First, the polysaccharide matrix solution was prepared by heating a quantitative amount of purified water to 45°C and stirring at a constant speed of 300 r / min for 40 min. Then, sodium alginate, carboxymethyl chitosan, and modified konjac glucomannan were added in sequence and stirred until all the powders were completely dissolved to form a uniform, transparent colloidal mother liquor without agglomerates, which ensures the uniform formation of the subsequent three-dimensional network structure.

[0034] Subsequently, functional microparticle dispersion pretreatment was carried out. The quantitative fermented Astragalus polysaccharide microparticles were ultrasonically dispersed at 120W for 5 minutes to break the microparticle aggregation. The dispersed microparticle system was then added to the above colloidal mother liquor, and the stirring speed was adjusted to 150r / min and stirred continuously for 15 minutes to make the microparticles uniformly dispersed in the colloidal system, thus obtaining a homogeneous mixed colloid.

[0035] Subsequently, a buffered composite crosslinking molding process was carried out. A composite buffer crosslinking solution with a mass fraction of 0.20% and a mass ratio of calcium chloride to sodium citrate of 1.2:0.8 was prepared and added to the mixed colloid at a low and uniform rate of 1.0 mL / min to avoid structural defects caused by instantaneous crosslinking. The mixture was allowed to stand at room temperature for 25 min for crosslinking to obtain a basic hydrogel with a dense structure and uniform pores.

[0036] Further functional modification of the inner and outer layers was carried out. The prepared base hydrogel was placed in a 0.5 mg / mL reduced glutathione aqueous solution and soaked at 4°C for 12 h to complete the uniform embedding of the inner layer antioxidant functional components, thereby achieving the construction of long-term antioxidant and oxidative stress damage blocking function of the inner layer of the hydrogel. Subsequently, the modified inner layer hydrogel was transferred to a phosphate buffer solution with a pH of 7.2 containing 0.3 mg / mL casein phosphopeptide and reacted continuously at 25°C and 120 r / min for 8 h to stably covalently graft casein phosphopeptide onto the outer layer of the hydrogel, giving the outer layer of the hydrogel the properties of targeted adhesion and promoting the healing of intestinal mucosal wounds.

[0037] Finally, the modified composite functional hydrogel was rinsed multiple times with sterile pure water to remove residual impurities on the surface, drained at a constant temperature to remove excess water, and cut and shaped according to medical standards to obtain the final intestinal repair hydrogel product.

[0038] Compared with other embodiments, the hydrogel three-dimensional network structure prepared in this embodiment has the densest structure, the optimal loading of functional components, and the best synergistic repair effect.

[0039] Example 4 The difference between this embodiment and Embodiment 1 is that, according to the mass fraction, the raw material composition in this embodiment is 52 parts sodium alginate, 32 parts carboxymethyl chitosan, 22 parts modified konjac glucomannan, 7 parts reduced glutathione, 4.5 parts casein phosphopeptide, 9 parts fermented astragalus polysaccharide microparticles, 1.3 parts calcium chloride, 0.9 parts sodium citrate, and 820 parts purified water, and the particle size of the fermented astragalus polysaccharide microparticles is controlled to be 300 nm.

[0040] Based on the raw material composition provided above, the preparation process of the hydrogel in this embodiment is as follows: First, the polysaccharide matrix solution was prepared by heating a quantitative amount of purified water to 48°C and stirring at a constant speed of 320 r / min for 42 min. Then, sodium alginate, carboxymethyl chitosan, and modified konjac glucomannan were added in sequence and stirred until all the powders were completely dissolved to form a uniform, transparent colloidal mother liquor without agglomerates, which ensures the uniform formation of the subsequent three-dimensional network structure.

[0041] Subsequently, functional microparticle dispersion pretreatment was carried out. The quantitative fermented Astragalus polysaccharide microparticles were ultrasonically dispersed at 130W for 6 minutes to break the microparticle aggregation. The dispersed microparticle system was then added to the above colloidal mother liquor, and the stirring speed was adjusted to 160r / min and stirred continuously for 16 minutes to make the microparticles uniformly dispersed in the colloidal system, thus obtaining a homogeneous mixed colloid.

[0042] Subsequently, a buffered composite crosslinking molding process was carried out. A composite buffer crosslinking solution with a mass fraction of 0.22% and a mass ratio of calcium chloride to sodium citrate of 1.3:0.9 was prepared and added to the mixed colloid at a low and uniform rate of 1.1 mL / min to avoid structural defects caused by instantaneous crosslinking. The mixture was allowed to stand at room temperature for 28 min for crosslinking to obtain a basic hydrogel with a dense structure and uniform pores.

[0043] Further functional modification of the inner and outer layers was carried out. The prepared base hydrogel was placed in a 0.55 mg / mL reduced glutathione aqueous solution and soaked at 3°C ​​for 13 h to complete the uniform embedding of the inner layer antioxidant functional components, thereby achieving the function of long-term antioxidant and blocking oxidative stress damage in the inner layer of the hydrogel. Subsequently, the modified inner layer hydrogel was transferred to a phosphate buffer solution with a pH of 7.2 containing 0.35 mg / mL casein phosphopeptide and reacted continuously at 26°C and 130 r / min for 8.5 h to stably covalently graft casein phosphopeptide onto the outer layer of the hydrogel, giving the outer layer of the hydrogel the properties of targeted adhesion and promoting the healing of intestinal mucosal wounds.

[0044] Finally, the modified composite functional hydrogel was rinsed multiple times with sterile pure water to remove residual impurities on the surface, drained at a constant temperature to remove excess water, and cut and shaped according to medical standards to obtain the final intestinal repair hydrogel product.

[0045] Example 5 The difference between this embodiment and Embodiment 1 is that, according to the mass fraction, the raw material composition in this embodiment is 55 parts sodium alginate, 35 parts carboxymethyl chitosan, 25 parts modified konjac glucomannan, 8 parts reduced glutathione, 5 parts casein phosphopeptide, 10 parts fermented astragalus polysaccharide microparticles, 1.4 parts calcium chloride, 1.0 part sodium citrate, and 850 parts purified water, and the particle size of the fermented astragalus polysaccharide microparticles is controlled to be 350 nm.

[0046] Based on the raw material composition provided above, the hydrogel preparation process in this embodiment is as follows: First, the polysaccharide matrix solution was prepared by heating a quantitative amount of purified water to 50°C and stirring at a constant speed of 350 r / min for 45 min. Then, sodium alginate, carboxymethyl chitosan, and modified konjac glucomannan were added in sequence and stirred until all the powders were completely dissolved to form a uniform, transparent colloidal mother liquor without agglomerates, which ensures the uniform formation of the subsequent three-dimensional network structure.

[0047] Subsequently, functional microparticle dispersion pretreatment was carried out. The quantitative fermented Astragalus polysaccharide microparticles were ultrasonically dispersed at 150W for 8 minutes to break the microparticle aggregation. The dispersed microparticle system was then added to the above colloidal mother liquor, and the stirring speed was adjusted to 180r / min and stirred continuously for 18 minutes to make the microparticles uniformly dispersed in the colloidal system, thus obtaining a homogeneous mixed colloid.

[0048] Subsequently, a buffered composite crosslinking molding process was carried out. A composite buffer crosslinking solution with a mass fraction of 0.25% and a mass ratio of calcium chloride to sodium citrate of 1.4:1.0 was prepared and added to the mixed colloid at a low and uniform rate of 1.2 mL / min to avoid structural defects caused by instantaneous crosslinking. The mixture was allowed to stand at room temperature for 30 min for crosslinking to obtain a basic hydrogel with a dense structure and uniform pores.

[0049] Further functional modification of the inner and outer layers was carried out. The prepared base hydrogel was placed in a 0.6 mg / mL reduced glutathione aqueous solution and soaked at 3°C ​​for 14 h to complete the uniform embedding of the inner layer antioxidant functional components, thereby realizing the long-term antioxidant and oxidative stress damage blocking function of the inner layer of the hydrogel. Subsequently, the modified inner layer hydrogel was transferred to a phosphate buffer solution with a pH of 7.2 containing 0.4 mg / mL casein phosphopeptide and reacted continuously at 27°C and 140 r / min for 9 h to stably covalently graft casein phosphopeptide onto the outer layer of the hydrogel, giving the outer layer of the hydrogel the properties of targeted adhesion and promoting the healing of intestinal mucosal wounds.

[0050] Finally, the modified composite functional hydrogel was rinsed multiple times with sterile pure water to remove residual impurities on the surface, drained at a constant temperature to remove excess water, and cut and shaped according to medical standards to obtain the final intestinal repair hydrogel product.

[0051] To verify the technical necessity of the ternary polysaccharide composite matrix, calcium-sodium composite buffer crosslinking architecture, layered functional loading structure, and embedded microbial community regulating particles of this invention, and to clarify the beneficial effects of each core structure on the mechanical properties, retention properties, antioxidant and anti-inflammatory properties, mucosal repair properties, and microbial community regulating properties of the hydrogel, this invention sets up three sets of single-variable comparative examples. All comparative examples are based on the optimal parameter example 3. The specific comparative example settings are as follows: Comparative Example 1 Compared with Example 3, this comparative example lacks the ternary polysaccharide composite matrix, omits the modified konjac glucomannan component, and simultaneously adjusts the amount of sodium alginate to 60 parts and the amount of carboxymethyl chitosan to 30 parts. It uses a traditional binary polysaccharide matrix system to replace the ternary interpenetrating network structure of the present invention. The remaining functional component ratios, crosslinking processes, layered modification processes, and molding processes are completely consistent with those of Example 3.

[0052] Comparative Example 2 Compared with Example 3, this comparative example lacks the calcium-sodium composite buffer crosslinking system, eliminates the sodium citrate buffer complexing component, uses only 1.2 parts of calcium chloride as a single crosslinking agent, and prepares the hydrogel using the traditional instantaneous calcium ion crosslinking process. The buffer-type controllable crosslinking mode of this invention is abandoned. The remaining matrix formulation, functional component loading process, and layered modification operation are completely consistent with Example 3.

[0053] Comparative Example 3 This comparative example serves as a baseline control group for existing technologies. It selects mainstream intestinal repair polysaccharide hydrogels publicly used in the field as control samples. These traditional hydrogels generally employ a binary polysaccharide matrix and a single calcium ion instantaneous cross-linking process. The functional components are homogeneously mixed, and there are no internal or external layered repair structures or microparticles for regulating the gut microbiota. They are currently conventional commercial products in the field of inflammatory bowel disease repair, providing a reference benchmark for the performance of existing technologies for the technical solution of this invention.

[0054] To objectively, comprehensively, and quantitatively evaluate the overall performance of the various embodiments and comparative samples of this invention, and to accurately verify the performance improvement brought about by this invention, this invention adopts standard testing methods commonly used in the field, unifies the test environment, test temperature, test equipment and operating procedures, and conducts parallel performance tests on all experimental and control group samples. Three parallel repeated tests are set up for each group of samples, and the average value of the parallel tests is taken as the valid test data, so as to comprehensively characterize the structural stability, lesion retention capacity, antioxidant activity, intestinal mucosal repair capacity and intestinal flora regulation capacity of the samples.

[0055] The specific experimental process is as follows: (1) The compressive strength of each sample was tested by a microcomputer-controlled universal testing machine under standard room temperature conditions. The maximum compressive strength of the hydrogel was accurately determined, thereby characterizing the deformation resistance and damage resistance stability of the three-dimensional network structure of the hydrogel.

[0056] (2) By constructing an in vitro simulation system that simulates the dynamic peristalsis and fluid flushing of the human gastrointestinal tract, each group of hydrogel samples were placed in a standardized artificial intestinal simulation solution and continuously incubated at a constant temperature for 24 hours. After incubation, the samples were taken out, dried, and weighed. The proportion of the remaining mass of the sample to the initial mass was calculated to obtain the 24-hour intestinal retention rate, which accurately evaluated the long-term retention stability and anti-fluid flushing ability of the hydrogel at the intestinal lesion site.

[0057] (3) The DPPH free radical scavenging rate was tested by standard ultraviolet spectrophotometry. The antioxidant activity was quantified by detecting the sample’s free radical scavenging efficiency, and the ability of hydrogel to inhibit intestinal oxidative stress and block the inflammatory cascade amplification was characterized.

[0058] (4) An in vitro mucosal repair experiment was conducted using the mature Caco-2 intestinal epithelial cell injury model. The cell culture environment and sample concentration were standardized. After continuous culture for 48 hours, the proportion of cell wound healing was detected to accurately evaluate the ability of each sample to target and repair the damaged intestinal mucosa.

[0059] (5) The gut microbiota of DSS-induced inflammation model mice was sequenced and analyzed using 16S rRNA high-throughput sequencing technology. The proportion of increase in the abundance of beneficial bacteria in the gut of mice after intervention of each group of samples was quantitatively detected, thereby characterizing the gut microbiota regulation ability of hydrogel.

[0060] The parallel performance test results of each set of examples and comparative samples are shown in Tables 1 and 2 below.

[0061] Table 1. Results of hydrogel structure and retention performance testing for each embodiment and comparative example.

[0062] As can be seen from Table 1, the comparative hydrogel samples showed obvious performance defects. Compared with the samples of the various embodiments of the present invention, their compressive strength was significantly reduced, their 24-hour intestinal retention rate was significantly decreased, their three-dimensional network structure was loose and their pores were disordered, and their resistance to deformation and intestinal erosion was weak, making them prone to structural damage and lesion loss.

[0063] Compared with the inferior comparative samples, the hydrogels of the present invention showed significant improvements in structural properties and intestinal retention performance: Example 1 achieved a compressive strength of 32.8 kPa and a 24-hour intestinal retention rate of 87.5%; Example 2 achieved a compressive strength of 31.2 kPa and a 24-hour intestinal retention rate of 86.1%; Example 3 achieved a compressive strength of 33.5 kPa and a 24-hour intestinal retention rate of 88.2%; Example 4 achieved a compressive strength of 30.9 kPa and a 24-hour intestinal retention rate of 85.8%; and Example 5 achieved a compressive strength of 32.1 kPa and a 24-hour intestinal retention rate of 86.9%. The hydrogels of each example group exhibited a dense and regular three-dimensional structure, excellent deformation resistance, and long-term retention under dynamic intestinal peristalsis and fluid flushing conditions, with significantly improved structural support integrity.

[0064] In contrast, the improvement in various structural and retention indicators of the comparative samples was significantly weaker than that of the embodiments of the present invention: Comparative Example 1 used a binary polysaccharide matrix instead of a ternary composite structure, with a compressive strength of only 22.4 kPa and a 24-hour intestinal retention rate of only 71.2%; Comparative Example 2 abandoned the buffered and controllable cross-linking architecture and adopted a single instantaneous cross-linking mode, with a compressive strength of 25.8 kPa and a 24-hour intestinal retention rate of 76.4%; Comparative Example 3 of the prior art had the worst overall performance, with a compressive strength of only 21.6 kPa and a 24-hour intestinal retention rate of only 69.8%. The hydrogel structure was loose and easily damaged, resulting in extremely poor stability of intestinal lesion retention and very limited improvement effect.

[0065] Furthermore, performance tests confirm that the intestinal repair hydrogel prepared by this invention can effectively optimize the three-dimensional network structure of the gel, significantly improving the mechanical stability of the hydrogel and its resistance to intestinal erosion and retention. This invention employs a ternary polysaccharide intercalation composite structure combined with a calcium-sodium buffered controllable cross-linking architecture, which avoids the structural defects of traditional hydrogels and solves the problem of structural loosening caused by instantaneous cross-linking, ensuring long-term stable retention of the hydrogel in the intestine. Compared with hydrogels with traditional structures, it possesses superior structural support and lesion retention effects.

[0066] Table 2. Results of hydrogel biorepair function tests for each embodiment and comparative example.

[0067] As can be seen from Table 2, the comparative hydrogel samples showed obvious functional defects. Compared with the samples of the various embodiments of the present invention, their DPPH free radical scavenging ability was greatly weakened, their intestinal mucosal repair efficiency was significantly reduced, their intestinal flora improvement effect was weak, and they had problems such as single function, poor targeting, and easy loss of active components, and could not achieve multi-dimensional intestinal damage repair.

[0068] Compared with the comparative samples, the hydrogel biorepair function of the present invention's embodiment groups was significantly improved: Example 1 achieved a DPPH clearance rate of 82.1%, a mucosal repair rate of 84.5%, and a gut microbiota improvement rate of 37.2%; Example 2 achieved a DPPH clearance rate of 80.8%, a mucosal repair rate of 83.6%, and a gut microbiota improvement rate of 39.5%; Example 3 achieved a DPPH clearance rate of 83.2%, a mucosal repair rate of 85.7%, and a gut microbiota improvement rate of 38.8%; Example 4 achieved a DPPH clearance rate of 81.5%, a mucosal repair rate of 86.2%, and a gut microbiota improvement rate of 36.5%; Example 5 achieved a DPPH clearance rate of 82.7%, a mucosal repair rate of 84.9%, and a gut microbiota improvement rate of 37.9%. All the embodiments can simultaneously achieve efficient antioxidant activity, mucosal wound repair, and gut microbiota homeostasis regulation, demonstrating balanced and excellent multi-dimensional gut repair performance.

[0069] In contrast, the improvement in various bioremediation indicators of the comparative samples was significantly weaker than that of the embodiments of the present invention: Comparative Example 1, without the synergistic support of ternary polysaccharides, had a DPPH clearance rate of only 73.6%, a mucosal repair rate of only 74.5%, and a microbial community improvement rate of only 25.3%; Comparative Example 2, using a traditional homogenization and mixing process, had a DPPH clearance rate of 76.2%, a mucosal repair rate of 77.8%, and a microbial community improvement rate of 28.1%; Comparative Example 3 of the existing technology had the weakest repair ability, with a DPPH clearance rate of only 72.1%, a mucosal repair rate of only 73.2%, and a microbial community improvement rate of only 23.5%, possessing only basic and weak repair effects, unable to achieve simultaneous improvement of oxidative damage, mucosal damage, and microbial community imbalance, and the repair effect was very limited.

[0070] Furthermore, performance tests confirm that the intestinal repair hydrogel prepared in this invention can effectively scavenge intestinal free radicals, inhibit oxidative stress damage, and efficiently promote the healing of intestinal mucosal wounds. Simultaneously, it steadily optimizes the intestinal flora structure and reshapes the intestinal microecological homeostasis. This invention employs a layered, differentiated functional loading design to combine fermented astragalus polysaccharide microparticles, which solves the technical problems of functional component loss and lack of targeted action caused by traditional homogenization and mixing processes. It achieves stepwise, multi-dimensional intestinal damage repair, exhibiting more comprehensive and superior biological repair efficacy compared to traditional single-function repair hydrogels.

[0071] Based on the data in Tables 1 and 2 and the corresponding technical mechanisms, it is clear that the ternary polysaccharide composite matrix and the calcium-sodium buffer crosslinking structure synergistically ensure the structural stability and long-term retention performance of the hydrogel, solving the problems of easy breakage, easy detachment, and short repair cycle of traditional hydrogels. The internal and external layered functional loading structure precisely matches the multi-level pathological damage in the intestine, achieving targeted and long-term effects of anti-inflammation, anti-oxidation, and mucosal repair. The fermented astragalus polysaccharide microparticles endow the material with unique microbial regulation capabilities, making up for the shortcomings of traditional materials in improving intestinal microecological imbalance. The differentiated performance of each embodiment proves that the present invention has a wide range of parameter adaptability and stable preparation process. Any ratio within the range can obtain a high-quality hydrogel with both structural and repair properties, and its comprehensive technical advantages are significantly superior to existing technical solutions.

[0072] To further verify the practical application value and in vivo efficacy of the hydrogel of this invention in the clinical repair treatment of inflammatory bowel disease, two clinically suitable dosage forms were prepared based on the sample of Example 3 with the best comprehensive performance: oral gel granules and rectal gel suppositories. In vivo animal efficacy tests were conducted using a standardized mouse ulcerative colitis model. Existing commercially available gel formulations were simultaneously set up as comparative examples. All experimental conditions, dosages, dosing cycles, and testing standards were standardized throughout the process to comprehensively evaluate the in vivo anti-inflammatory and mucosal repair effects of the different dosage forms of this invention. The specific application examples and experimental procedures are as follows: Application Example 1 This application example specifically prepares hydrogel into an oral gel particle dosage form, which includes: aseptically cutting, low-temperature constant temperature drying, and standard sieving of the finished hydrogel prepared in Example 3 to obtain oral gel particles with uniform particle size of 0.8-1.2 mm. This dosage form can fully cover the gastrointestinal mucosa and is suitable for the repair treatment of extensive and diffuse intestinal inflammatory barrier damage.

[0073] Application Example 2 This application example specifically prepares the hydrogel into a rectal gel suppository dosage form, which includes: pouring and molding the sol-state hydrogel prepared in Example 3 into a standardized mold, setting it at low temperature, and aseptically encapsulating it to prepare a rectal gel suppository. This dosage form can accurately target and adhere to lesions in the distal colon and rectum, has excellent local retention, and is suitable for targeted repair treatment of localized distal intestinal inflammation.

[0074] Application of comparative examples Commercially available conventional intestinal repair hydrogel formulations were selected as control drugs, and the dosage, administration method, administration cycle, and animal model construction method were completely consistent with the application examples of this invention.

[0075] Healthy SPF-grade C57 mice aged 6-8 weeks were randomly divided into a blank control group, a DSS inflammation model group, an oral gel granule administration group, a rectal gel suppository administration group, and an existing technology formulation administration group. Multiple parallel mice were set up in each group to ensure the reliability of the experiment. Except for the blank control group, which was fed normally without treatment, all other groups of mice were fed 3.0% sodium dextran sulfate in free drinking water for 7 days to establish a stable ulcerative colitis model. After successful modeling, each administration group was given an equal amount of the test drug every other day for 7 consecutive days. The blank control group and the model group were given an equal amount of physiological saline for intervention. The survival status and inflammatory manifestations of the mice were continuously observed during the experimental period. After the experiment, the mice were uniformly sampled and tested for three core efficacy indicators: disease activity index, intestinal mucosal damage score, and inhibition rate of core pro-inflammatory factors in the intestine, to comprehensively evaluate the in vivo repair effect.

[0076] The in vivo efficacy test results of each group of application test samples are shown in Table 3 below. The lower the DAI disease activity index and intestinal mucosal damage score, the milder the intestinal inflammation symptoms and the better the mucosal repair effect in mice. The higher the inflammatory factor inhibition rate, the stronger the anti-inflammatory activity of the sample in vivo.

[0077] Table 3, based on the results of the animal experiments, shows that the mice in the DSS-induced inflammation model group exhibited significant inflammatory damage in their intestines. Compared with the blank control group, the mice had severe intestinal mucosal damage, disordered intestinal structure, significantly increased DAI disease activity index and intestinal mucosal damage score, and a large amount of pro-inflammatory factors were expressed in the intestines, indicating severe damage to the intestinal barrier function.

[0078] Compared to the inflammation model group, the intestinal inflammatory damage in mice in each application example of this invention was significantly improved: Rectal gel suppository application example 2 significantly reduced the degree of intestinal inflammation in mice, with the DAI disease activity index decreasing to 0.98, the intestinal mucosal damage score decreasing to 1.82, and the inhibition rate of intestinal inflammatory factors reaching 82.3%. It can precisely repair distal intestinal mucosal damage, reduce local inflammatory response, and significantly improve the integrity of the intestinal barrier; Oral gel granule application example 1 can achieve balanced repair of inflammation throughout the entire intestine, with the DAI disease activity index at 1.12, the intestinal mucosal damage score at 2.15, and the inhibition rate of inflammatory factors reaching 78.6%. It can comprehensively improve extensive intestinal inflammatory damage and effectively alleviate the pathological symptoms of intestinal inflammation in mice.

[0079] In comparison, the improvement in various efficacy indicators of commercially available gel formulations prepared using existing traditional processes was significantly weaker than that of the application examples of this invention: the DAI disease activity index was as high as 2.46, the intestinal mucosal damage score was as high as 3.95, the inflammatory factor inhibition rate was only 56.2%, the repair of intestinal mucosal damage in mice was incomplete, the inflammation reduction effect was limited, and the intestinal barrier improvement effect was poor.

[0080] Animal experiments further confirm that the intestinal repair hydrogel prepared in this invention can effectively improve DSS-induced ulcerative colitis damage in mice, efficiently inhibit the expression of pro-inflammatory factors in the intestine, reduce intestinal inflammatory response, and precisely repair damaged intestinal mucosa and reshape intestinal barrier function. This invention employs a ternary polysaccharide composite structure, a calcium-sodium buffered controllable cross-linking mode, and an inner and outer layered functional loading structure, ensuring long-term retention of the hydrogel in the intestine and targeted exertion of repair and anti-inflammatory effects. Embedded microbial regulation microparticles can improve intestinal pathological conditions from multiple dimensions. Compared with traditional single-repair hydrogel formulations, it has superior in vivo intestinal repair and anti-inflammatory therapeutic effects, and different dosage forms can be adapted to different intestinal inflammation treatment scenarios, making it more suitable for clinical applications.

[0081] Furthermore, the biocompatibility and in vivo safety of biomedical materials are prerequisites for clinical translation. To verify the safety of the hydrogel of this invention, an in vivo biocompatibility test was conducted using the sample from the optimal embodiment 3. Healthy mice were randomly divided into an experimental group and a blank control group. Mice in the experimental group were given the hydrogel of this invention every other day for continuous intervention, while mice in the blank control group were fed normally without special treatment. After 10 days of continuous feeding, the mice were sacrificed, and tissue sections and H&E staining of the five major organs (heart, liver, spleen, lung, and kidney) were collected for observation of organ tissue structure and cell state. The experimental results showed that the tissue structure of each organ in the experimental group mice was intact and clear, without inflammatory cell infiltration, tissue edema, or necrosis. The physiological state of the organs was not significantly different from that of the blank control group, which fully demonstrates that the intestinal repair hydrogel prepared by this invention has excellent biocompatibility, no in vivo toxic side effects, fully meets the safety standards for medical repair materials, and has a good foundation for clinical translation.

[0082] Therefore, this invention constructs a uniform and mechanically stable three-dimensional cross-linked network by using a ternary polysaccharide matrix composed of sodium alginate, carboxymethyl chitosan, and modified konjac glucomannan, along with a calcium chloride-sodium citrate composite cross-linking component. This solves the defects of traditional hydrogels, such as uneven gel formation, weak mechanical properties, easy breakage and detachment in the gastrointestinal tract, and short retention time in lesions. Simultaneously, it employs a differentiated layered loading mode, embedding antioxidant components in the inner layer and covalently grafting mucosal repair components in the outer layer, to achieve targeted and layered intestinal anti-inflammatory and mucosal repair, breaking through the limitations of traditional hydrogels with mixed release of functional components, poor repair targeting, and single layering. Furthermore, it utilizes embedded fermented astragalus polysaccharide microparticles to achieve intestinal microecological regulation, achieving dual synergistic repair of physical and microecological barriers. This improves intestinal inflammation from the root causes of pathological structure and microenvironment, effectively solving the problems of incomplete wound repair and easy recurrence of inflammation. Overall, it improves the stability of the hydrogel structure, retention of intestinal lesions, repair precision, and long-term effectiveness.

[0083] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0084] This document uses specific examples to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, those skilled in the art will recognize that, based on the ideas of the present invention, there will be changes in the specific implementation methods and application scope. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A hydrogel for repairing the intestinal barrier, characterized in that, It includes a ternary polysaccharide matrix, a composite buffer crosslinking component, a layered loaded functional component, and microbial community regulating microparticles; The ternary polysaccharide matrix is ​​composed of sodium alginate, carboxymethyl chitosan, and modified konjac glucomannan; The composite buffer crosslinking component is a combination of calcium chloride and sodium citrate; The layered loading functional components include an inner layer of embedded antioxidant functional components and an outer layer of covalently grafted mucosal repair functional components. The microbial community regulating microparticles are fermented Astragalus polysaccharide microparticles embedded in the ternary polysaccharide matrix; The content of each raw material component by weight is as follows: sodium alginate 45-55 parts, carboxymethyl chitosan 25-35 parts, modified konjac glucomannan 15-25 parts, antioxidant functional component 4-8 parts, mucosal repair functional component 3-5 parts, fermented astragalus polysaccharide microparticles 6-10 parts, calcium chloride 1.0-1.4 parts, sodium citrate 0.6-1.0 parts, and purified water 750-850 parts.

2. The hydrogel according to claim 1, characterized in that, The antioxidant functional component is reduced glutathione, and the mucosal repair functional component is casein phosphopeptide.

3. The hydrogel according to claim 1, characterized in that, The particle size of the fermented Astragalus polysaccharide microparticles is 150~350nm.

4. A method for preparing a hydrogel as described in any one of claims 1 to 3, characterized in that, Includes the following steps: S1. Heat purified water under stirring, add sodium alginate, carboxymethyl chitosan and modified konjac glucomannan in sequence, and continue stirring until all raw materials are completely dissolved to obtain a homogeneous and transparent colloidal mother liquor. S2. After ultrasonic dispersion pretreatment, fermented Astragalus polysaccharide microparticles are added to colloidal mother liquor and stirred continuously to make the microparticles uniformly dispersed in the colloid, thus obtaining a mixed colloid with uniform components. S3. Prepare a calcium chloride and sodium citrate composite crosslinking solution and add it dropwise into the mixed colloid at a uniform rate. The crosslinking is completed by standing to obtain a basic hydrogel with a complete structure. S4. The prepared basic hydrogel was subjected to inner layer antioxidant functional component embedding treatment and outer layer mucosal repair functional component covalent grafting treatment to form a functional load structure with inner and outer layers. S5. The hydrogel that has undergone layered functional modification is rinsed, drained, and cut into shape to obtain the final hydrogel product.

5. The preparation method according to claim 4, characterized in that, In step S1, the water temperature is controlled at 40~50℃, the stirring speed is 250~350r / min, and stirring is continued for 35~45min.

6. The preparation method according to claim 4, characterized in that, In step S2, when pretreating the fermented Astragalus polysaccharide microparticles, ultrasonic dispersion at 100-150W power is performed for 3-8 minutes, followed by stirring in colloidal mother liquor at 120-180r / min for 12-18 minutes.

7. The preparation method according to claim 4, characterized in that, In step S3, a calcium chloride-sodium citrate composite crosslinking solution with a mass fraction of 0.15%~0.25% is prepared and added dropwise at a rate of 0.8~1.2 mL / min. The solution is then allowed to stand for crosslinking at room temperature for 20~30 min. The mass ratio of calcium chloride to sodium citrate in the composite crosslinking solution is 1.0~1.4:0.6~1.

0.

8. The preparation method according to claim 4, characterized in that, In step S4, the base hydrogel is placed in an aqueous solution of reduced glutathione with a concentration of 0.4~0.6 mg / mL and soaked at 3~5℃ for 10~14 h to complete the inner layer embedding. Then, the hydrogel with the inner layer embedded is placed in a phosphate buffer solution with a pH of 7.2~7.6 containing 0.2~0.4 mg / mL casein phosphopeptide and shaken at 23~27℃ and 100~140 r / min for 7~9 h to covalently graft and fix the mucosal repair functional components onto the outer surface of the hydrogel, thus completing the layered functional modification of the hydrogel.

9. The use of a hydrogel as described in any one of claims 1 to 3 in the preparation of a medicament for treating inflammatory bowel disease.

10. The application according to claim 9, characterized in that, The drug is available in the form of oral gel granules or rectal gel suppositories.

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