Hydrogel system, preparation method thereof and intragastric retention system

Abstract

The invention discloses a hydrogel system, a preparation method thereof and an intragastric retention system, and relates to the technical field of medical instruments. The hydrogel system is of a core-shell structure and comprises a core expansion layer, a stable protection layer and an intestinal juice response layer from inside to outside; wherein the volume of the hydrogel system after swelling treatment for 10 minutes in an environment with the pH value of 1.0-1.3 is greater than 50 times of the volume before swelling, the swelling property is excellent, and the retention time of the hydrogel system in a body is prolonged; the swelling speed is adjusted by adjusting the particle size of the water-absorbing polymer, and the final volume is adjusted by adjusting the amount of the water-absorbing polymer. In addition, the hydrogel system is good in mechanical performance and can tolerate mechanical peristalsis of the stomach for a long time; the preparation method has the advantages of simple process, strong environmental responsiveness and high stability, can realize controllable dehydration or degradation in an intestinal alkaline environment, and keeps structural integrity under a stomach acidic condition; the porous structure allows gastric juice to permeate and prevents structure disintegration; the biological safety is high, and a feasible strategy is provided for clinical application.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and more specifically, to hydrogel systems and their preparation methods, and gastric retention systems. Background Technology

[0002] As an important drug delivery platform, intragastric retention systems have broad application prospects in obesity treatment, gastric disease management, and prolonging the intragastric release time of drugs. An ideal intragastric retention system needs to meet the following requirements: easy to swallow, rapid expansion to avoid expulsion through the pylorus, able to withstand the harsh environment of the stomach (strong acidity and mechanical peristalsis), stable long-term retention (at least 10 days), and controllable expulsion when needed.

[0003] The existing intragastric expansion technologies have the following shortcomings: (1) Insufficient expansion performance: Existing swallowable expandable hydrogels usually take several days to expand, and the final volume can only reach a maximum of 10 times the original size, making it easy to pass through the body and be excreted. (2) Poor mechanical properties: Existing materials are often soft and lack the strength to withstand intragastric pressure, making it difficult to maintain structural integrity in the harsh environment of the stomach for a long time. (3) Weak environmental responsiveness: Most systems do not have intelligent responsiveness and cannot achieve controlled dehydration or degradation under specific environmental stimuli (such as pH changes). (4) Biosafety issues: Some hydrogels using chemical cross-linking agents (such as glutaraldehyde) may have toxicity issues, limiting their clinical application.

[0004] Therefore, there is an urgent need in this field to develop a smart hydrogel system that can simultaneously expand rapidly in the stomach, remain stably for a long period of time, and be rapidly dehydrated and discharged in the intestinal fluid environment.

[0005] In view of this, the present invention is proposed. Summary of the Invention

[0006] The purpose of this invention is to provide a hydrogel system and its preparation method, as well as a gastric retention system, to solve or improve the above-mentioned technical problems.

[0007] This invention is implemented as follows: In a first aspect, embodiments of the present invention provide a hydrogel system, the hydrogel system having a core-shell structure, including a core expansion layer, a stabilizing protective layer, and an intestinal fluid responsive layer from the inside out; Among them, the volume of the hydrogel system after swelling treatment for 10 min in an environment with pH 1.0-1.3 is greater than 50 times the volume before swelling.

[0008] Secondly, embodiments of the present invention provide a method for preparing the hydrogel system as described above, comprising the following steps: After mixing the water-absorbing polymer and the pore-forming agent in a certain proportion, the mixture is reacted at a temperature of 65℃-75℃ for 1.5h-2.5h, and then freeze-dried at a temperature of -45℃ to -55℃ for 20h-25h to obtain the core expansion layer material. Chitosan, polyacrylate and gel polysaccharide are mixed in proportion and reacted at pH 3.5-4.5 for 3.5-4.5 hours to obtain a stable protective layer material. Polyvinyl alcohol and 3,4-dihydroxyphenylalanine were mixed in a certain proportion and reacted at pH 7.0-7.5 for 1-12 hours to obtain the intestinal fluid responsive layer material. After assembling the prepared core expansion layer material, stable protective layer material, and intestinal fluid responsive layer material, the hydrogel system was obtained by freeze-drying at a temperature of -45℃ to -55℃ for 45h-55h.

[0009] Thirdly, embodiments of the present invention provide a gastric retention system, including the hydrogel system as described above or the hydrogel system prepared by the aforementioned preparation method.

[0010] The present invention has the following beneficial effects: The hydrogel system provided in this invention has excellent swelling performance and can rapidly swell to more than 50 times its original volume in a short time, thus extending its residence time in the body. The swelling rate can be adjusted by regulating the particle size of the absorbent polymer, and the final volume can be adjusted by regulating the amount of absorbent polymer in the capsule.

[0011] The hydrogel system has the following characteristics: good mechanical properties, which can withstand gastric mechanical peristalsis for a long time; strong environmental responsiveness and high stability, which can achieve controlled dehydration or degradation under specific environmental stimuli (such as the alkaline environment of the intestine (pH≥6.8)) and maintain structural integrity under acidic conditions in the stomach; pore control, which allows gastric juice to permeate through the porous structure (pore size 50-200μm) while preventing structural disintegration; and high biosafety, providing a feasible strategy for clinical application. Attached Figure Description

[0012] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0013] Figure 1 This is a schematic diagram of the process for preparing the hydrogel system; Figure 2 A schematic diagram of the process for preparing the core expansion layer material; Figure 3 A schematic diagram of the process for preparing a stable protective layer material; Figure 4 A schematic diagram of the process for preparing the intestinal fluid responsive layer material; Figure 5 A diagram showing the state of the hydrogel system after water injection into the stomach of a Bama pig; Figure 6 This is a diagram showing the state of the hydrogel system in the stomach of a Bama pig after 72 hours. Detailed Implementation

[0014] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0015] The hydrogel system provided in this invention has the characteristics of rapid expansion in the stomach, long-term stable retention, and rapid dehydration and excretion in the intestinal fluid environment. Specific implementation methods are as follows: In a first aspect, embodiments of the present invention provide a hydrogel system, the hydrogel system having a core-shell structure, including a core expansion layer, a stabilizing protective layer, and an intestinal fluid responsive layer from the inside out; Among them, the volume of the hydrogel system after swelling treatment for 10 min in an environment with pH 1.0-1.3 is greater than 50 times the volume before swelling.

[0016] The hydrogel system provided in this invention has excellent swelling properties, and can rapidly swell to more than 50 times its original volume in a short time, thus prolonging its residence time in the body; it has good mechanical properties and can withstand gastric mechanical peristalsis for a long time; it has strong environmental responsiveness and can achieve controllable dehydration or degradation under specific environmental stimuli (such as pH changes); it has high biosafety and provides a feasible strategy for clinical application.

[0017] In an optional embodiment, the core expansion layer comprises a water-absorbing polymer and a pore-forming agent in a mass ratio of (1-5):1.

[0018] Hydrosorbent polymers contain a large number of hydrophilic groups, such as hydroxyl-OH, carboxyl-COOH, and amide-CONH2, which provide a three-dimensional network framework (crosslinked network) for hydrogel systems, as well as providing hydrophilicity and water absorption capacity. In addition, the type and crosslinking density of hydrosorbent polymers directly determine the mechanical properties, chemical stability, and biocompatibility of hydrogels.

[0019] Pore-forming agents themselves typically do not participate in the formation of the final hydrogel network. Instead, they are introduced during the preparation process and subsequently removed through specific methods (such as washing, dissolution, or sublimation), leaving cavities in the solid framework. Introducing pores usually reduces the density of the material, making the hydrogel lighter and softer, but at the cost of mechanical strength.

[0020] This invention adjusts the final volume of the hydrogel system and ensures its final mechanical properties by adjusting the amount of water-absorbing polymer in the core expansion layer; and the reasonable setting of the mass ratio of the two is conducive to the formation of an ideal porous structure in the hydrogel system.

[0021] For example, in the core expansion layer, the mass ratio of the water-absorbing polymer to the pore-forming agent is selected from any one of 1:1, 2:1, 3:1, 4:1 and 5:1, or other values ​​within the range of (1-5):1.

[0022] The swelling rate can be adjusted by regulating the particle size of the water-absorbing polymer. The smaller the particle size, the larger the contact area with the aqueous solution, and the faster the expansion rate.

[0023] In an optional embodiment, the particle size of the water-absorbing polymer is 100μm-150μm; It should be noted that the swelling rate of the water-absorbing polymer reaches its peak when the particle size is in the range of 100μm-150μm, and the volume after swelling is more than 50 times the volume before swelling. Although the initial swelling is fast when the particle size is less than 100μm, the final swelling ratio is low; the swelling rate slows down significantly when the particle size is greater than 200μm. For example, the particle size of the water-absorbing polymer can be selected from any one of 100μm, 110μm, 120μm, 130μm, 140μm, and 150μm, or other values ​​in the range of 100μm-150μm.

[0024] Composition optimization: An ideal porous structure is formed when the mass ratio of PAAS to KGM is 3:1, with a porosity of 85.3±2.7%, which is much higher than that of a single PAAS system (42.5±3.1%). And / or, the porosity of the core expansion layer is 82.6%-88%.

[0025] The pore-forming agent is washed out after hydrogel formation, leaving behind numerous cavities and interconnected channels. These pores provide ample space and convenient pathways for water molecules to enter and be stored, increasing the water absorption capacity and speed of the hydrogel system and ensuring rapid swelling of the hydrogel.

[0026] In an optional embodiment, the water-absorbing polymer is selected from at least one of sodium polyacrylate, polyacrylamide, polyvinyl alcohol, starch-acrylic acid graft copolymer, sodium polystyrene sulfonate, and carboxymethyl cellulose. And / or, the pore-forming agent is selected from at least one of konjac glucomannan, xanthan gum, guar gum, sodium alginate, chitosan and carrageenan.

[0027] In an optional implementation, the stabilizing protective layer is composed of a pH-sensitive composite hydrogel; Preferably, the stabilizing protective layer comprises chitosan, polyacrylate and gel polysaccharide in a mass ratio of (2-5):(1-3):1.

[0028] It should be noted that the stabilizing protective layer is a physical cross-linked network formed by chitosan, polyacrylate, and gel polysaccharide. It has strong mechanical strength and can withstand the pressure of gastric peristalsis, with a compressive strength of over 85.6 kPa. It also has strong stability in acidic environments, maintaining structural integrity under acidic conditions in the stomach. Furthermore, it features porosity control, allowing gastric juice to permeate through its porous structure (pore size of 50 μm-200 μm) while preventing structural disintegration.

[0029] For example, in the stabilizing protective layer, the mass ratio of chitosan, polyacrylate and gel polysaccharide is selected from any one of 2:1:1, 2:2:1, 3:1:1, 3:3:1, 3:3:1, 4:1:1, 4:3:1, 5:1:1, 5:2:1 and 5:3:1, or other values ​​within the range of (2-5):(1-3):1.

[0030] In an optional embodiment, the intestinal fluid response layer comprises polyvinyl alcohol and 3,4-dihydroxyphenylalanine in a mass ratio of 1:(3-8).

[0031] The intestinal fluid-responsive layer is composed of a pH-sensitive catechol-modified polymer, specifically a PVA (PVA-DP) hydrogel modified with 3,4-dihydroxyphenylalanine (DOPA, a bioactive molecule containing both catechol (catechol) and amino acid groups). This layer remains stable in the acidic environment of the stomach but rapidly dissolves in the alkaline environment of the intestine (pH ≥ 6.8), triggering rapid dehydration of the core layer. This layer achieves wet adhesion through hydrogen bonding between catechol groups and tissues, while undergoing structural changes in the alkaline environment leading to dissolution.

[0032] For example, in the intestinal fluid response layer, the mass ratio of polyvinyl alcohol and 3,4-dihydroxyphenylalanine is selected from any one of 1:3, 1:4, 1:4.5, 1:5, 1:6, 1:6.5, 1:7 and 1:8, or other values ​​in the range of 1:(3-8).

[0033] Secondly, embodiments of the present invention provide a method for preparing the hydrogel system as described above, comprising the following steps: After mixing the water-absorbing polymer and the pore-forming agent in a certain proportion, the mixture is reacted at a temperature of 65℃-75℃ for 1.5h-2.5h, and then freeze-dried at a temperature of -45℃ to -55℃ for 20h-25h to obtain the core expansion layer material. Chitosan, polyacrylate and gel polysaccharide are mixed in proportion and reacted at pH 3.5-4.5 for 3.5-4.5 hours to obtain a stable protective layer material. Polyvinyl alcohol and 3,4-dihydroxyphenylalanine were mixed in a certain proportion and reacted at pH 7.0-7.5 for 1-12 hours to obtain the intestinal fluid responsive layer material. After assembling the prepared core expansion layer material, stable protective layer material, and intestinal fluid responsive layer material, the hydrogel system was obtained by freeze-drying at a temperature of -45℃ to -55℃ for 45h-55h.

[0034] In an optional embodiment, when preparing the core expansion layer material, a suspension of 18% (w / v)-25% (w / v) is prepared by mixing the water-absorbing polymer and the pore-forming agent; after freeze-drying, a porous core expansion layer material is prepared.

[0035] And / or, when preparing the stable protective layer material, chitosan, polyacrylate and gel polysaccharide are mixed in solution form respectively; The chitosan solution comprises a chitosan acetate solution of 1.2% (w / v) to 2.5% (w / v), the polyacrylate solution comprises a polyacrylate aqueous solution of 3% (w / v) to 8% (w / v), and the gel polysaccharide solution comprises a gel polysaccharide aqueous solution of 1% (w / v) to 5% (w / v); the concentration of the acetate solution is 0.6% (v / v) to 1.5% (v / v). In other embodiments of the present invention, the concentration may be reasonably adjusted according to actual needs.

[0036] During the mixing and reaction of the solutions, a stable physical cross-linked network is formed through self-assembly.

[0037] Preferably, the gel polysaccharide solution is prepared under water bath conditions at a temperature of 85℃-95℃; And / or, when preparing the intestinal fluid responsive layer material, polyvinyl alcohol is added in solution form, the polyvinyl alcohol solution comprising 8% (w / v)-12% (w / v) aqueous polyvinyl alcohol solution. DOPA is grafted onto the PVA network via a simple solvent gradient displacement method, and the pH is adjusted to 7.4 to partially oxidize the catechol groups to form crosslinks.

[0038] For example, the operation steps of the solvent gradient displacement method in this embodiment of the invention are as follows: Place the PVA aqueous solution containing DOPA on a magnetic stirrer and stir at a speed of 400 rpm-600 rpm; Then anhydrous ethanol was slowly added dropwise to the PVA / DOPA mixture at a rate of 1 mL / min to 2 mL / min; the volume ratio of ethanol to aqueous solution was 1:1 to 1:3. Once the mixture forms a non-flowing, gel-like white precipitate / curd, stop stirring; then allow the entire system to stand at room temperature for 2-12 hours to complete the solvent gradient replacement.

[0039] It should be noted that, in other embodiments of the present invention, the operation steps of the solvent gradient displacement method and the raw materials and proportions used can be reasonably adjusted according to actual needs.

[0040] In an optional embodiment, the assembly of the hydrogel system includes the following steps: The core expansion layer material is placed in the center of the mold of the stabilizing protective layer, the stabilizing protective layer material is injected and gelled; after the gelled stabilizing protective layer is coated with an intestinal fluid response layer solution, it is freeze-dried.

[0041] In an optional implementation, assembly can be performed after the core expansion layer material, the stabilizing protective layer material, and the intestinal fluid response layer material have been prepared, or assembly can be performed during the preparation process.

[0042] Thirdly, embodiments of the present invention provide a gastric retention system, including the hydrogel system as described above or the hydrogel system prepared by the preparation method described above.

[0043] In an optional embodiment, the gastric retention system includes a hydrogel system having at least one of the following application methods: Method 1: The hydrogel system, after being soaked in an environment with a pH of 1.2-3.0 for 72 hours, exhibits a compressive strength ≥ 92.3% of the initial compressive strength and an elastic modulus ≥ 89.8% of the initial elastic modulus. Method 2: The mass loss rate of the hydrogel system after immersion in an environment with a pH of 1.2-3.0 for 24 hours is ≤5.2%; Method 3: The hydrogel system begins to dissolve in an environment with a pH of 6.8-7.4 within ≤15 minutes; Method 4: The volume of the hydrogel system decreased by more than 20% after swelling treatment in an environment with pH 6.8-7.4 for 2 hours.

[0044] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0045] Example 1 This embodiment provides a hydrogel system, the preparation of which includes the following steps: (1) Preparation of core expansion layer material A water-absorbing polymer (sodium polyacrylate, PAAS) and a pore-forming agent (konjac glucomannan, KGM) were mixed at a mass ratio of 3:1. Deionized water was then added to form a 20% (w / v) homogeneous suspension. The mixture was stirred at 70°C for 2 hours to ensure thorough mixing. Finally, it was freeze-dried (-50°C, 24 hours) to form a porous core expansion layer material. A schematic diagram of the preparation process is shown below. Figure 2 .

[0046] (2) Preparation of stable protective layer material Chitosan (CS) was dissolved in 1% (v / v) acetic acid solution to form a 2% (w / v) solution; polyacrylate (PAAS) was dissolved in deionized water to form a 5% (w / v) solution; gel polysaccharide (CUR) was dissolved in deionized water to form a 3% (w / v) solution, and heated in a 90°C water bath to form a thermally irreversible gel core; the CS solution, PAAS solution, and CUR gel were mixed in a ratio of (4:2:1), stirred for 4 hours under acidic conditions (pH 4.0) to allow self-assembly, poured into a mold, and gelled for 2.5 hours to form a shell structure; wherein, the mold contains the porous core expansion layer material obtained in step (1). A schematic diagram of the preparation process is shown below. Figure 3 .

[0047] (3) Preparation of intestinal fluid response layer material Polyvinyl alcohol (PVA) was dissolved in deionized water to form a 10% (w / v) solution; 3,4-dihydroxyphenylalanine (DOPA) (PVA to DOPA mass ratio 1:5) was added; DOPA was grafted onto the PVA network using a simple solvent gradient displacement method; the pH was adjusted to 7.4 to partially oxidize the catechol groups to form crosslinks, thus obtaining the intestinal fluid responsive layer material. A schematic diagram of the preparation process is shown below. Figure 4 .

[0048] The operation steps of the solvent gradient replacement method are as follows: Place the PVA aqueous solution containing DOPA on a magnetic stirrer and stir at 500 rpm; Then, anhydrous ethanol was slowly added dropwise to the PVA / DOPA mixture at a rate of 1.5 mL / min; the volume ratio of ethanol to aqueous solution was 1:2; thus completing the solvent gradient displacement.

[0049] Once the mixture forms a non-flowing, gel-like white precipitate / curd, stop stirring; then let the entire system stand at room temperature for 6.5 hours.

[0050] (4) Preparation of hydrogel system The intestinal fluid responsive layer material obtained in step (3) was completely coated onto the outer layer of the shell structure treated by gelation in step (2), with a coating thickness of 8 μm; the final porous structure was formed by freeze-drying (-50℃, 48 hours); and then cut into particles with a particle size of 150 μm. A schematic diagram of the preparation process is shown below. Figure 1 .

[0051] Example 2 This embodiment provides a hydrogel system, the preparation steps of which are the same as those in Example 1, the only difference being: (1) preparation of the core expansion layer material. The mass ratio of sodium polyacrylate (PAAS) to konjac glucomannan (KGM) is 1:1.

[0052] Example 3 This embodiment provides a hydrogel system, the preparation steps of which are the same as those in Example 1, the only difference being: (1) preparation of the core expansion layer material. The water-absorbing polymer is polyacrylamide, and the void-forming agent is guar gum.

[0053] Example 4 This embodiment provides a hydrogel system, the preparation steps of which are the same as those in Example 1, the only difference being: (2) preparation of a stable protective layer material. The CS solution, PAAS solution and CUR gel in the stabilizing protective layer are mixed in a ratio of 2:1:1.

[0054] Example 5 This embodiment provides a hydrogel system, the preparation steps of which are the same as those in Example 1, the only difference being: (3) preparation of intestinal fluid responsive layer material. The mass ratio of PVA to DOPA in the intestinal fluid response layer is 1:3.

[0055] Example 6 This embodiment provides a hydrogel system, the preparation steps of which are the same as those in Example 1, the only difference being: (4) preparation of the hydrogel system The final absorbent polymer has a particle size of 100 μm.

[0056] Comparative Example 1 This comparative example provides a hydrogel system whose preparation steps are the same as in Example 1, except that: Missing step (3) is to prepare the intestinal fluid response layer material to obtain a hydrogel system without the intestinal fluid response layer.

[0057] Experimental Example 1 This experiment tested the swelling properties of the hydrogel systems prepared in Examples 1-6 and compared them with traditional carboxymethyl cellulose (CMC) hydrogels.

[0058] Swelling performance test method: The hydrogel system and CMC prepared in Example 1 were placed in simulated gastric juice SGF (pH=1.2) respectively, and the swelling volume ratio and swelling rate at different time points were detected. The results are shown in Table 1.

[0059] Swelling volume ratio: weight after swelling / initial dry weight; swelling rate: average increase in swelling rate per unit time.

[0060] Table 1. Swelling properties of the core expansion layer in simulated gastric fluid (pH 1.2)

[0061] As can be seen from the data in Table 1, the prepared water-absorbing polymer can reach approximately 100 times its original volume within 10 minutes, significantly faster than traditional gastric retention hydrogels (which typically take several hours to several days). This rapid expansion mechanism ensures that the system reaches the pyloric blockade size (>12 mm) before the gastric emptying cycle, effectively preventing premature expulsion.

[0062] Experiment Example 2 This experimental example tested the mechanical properties of the hydrogel systems prepared in Examples 1-6 and Comparative Example 1, and compared them with traditional carboxymethyl cellulose (CMC) hydrogels. It should be noted that the continuous pressure generated by gastric peristalsis requires the gastric retention system to possess excellent mechanical properties.

[0063] Mechanical property testing method: The hydrogel systems and CMC prepared in Examples 1-6 and Comparative Example 1 were immersed in simulated gastric juice SGF (pH=1.2) for 72 hours. After filtering out the excess liquid, mechanical and rheological properties were tested. The mechanical property results of Examples 1-6 are shown in Table 2, and the mechanical property results of Comparative Example 1 and carboxymethyl cellulose (CMC) hydrogel are shown in Table 3.

[0064] Table 2 Mechanical property parameters of the hydrogel systems in Examples 1-6

[0065] Table 3 Mechanical property parameters of Comparative Example 1 and CMC hydrogel

[0066] As can be seen from the data in Tables 2 and 3, the hydrogel system of this invention exhibits excellent mechanical properties. After immersion in a simulated gastric environment for 72 hours, its compressive strength still retains more than 90% of its initial value, indicating that the hydrogel system prepared by this invention can withstand gastric mechanical peristalsis for a long time. It also exhibits distinct differentiated behavior in different pH environments, which is the key to achieving long-term gastric retention and intestinal-triggered expulsion.

[0067] Experimental Example 3 In this experiment, the hydrogel systems prepared in Examples 1-6 and Comparative Example 1 were subjected to mass loss tests in simulated gastric fluid (pH=1.2-3.0) and simulated intestinal fluid (pH=6.8-7.4), respectively, and were compared with traditional carboxymethyl cellulose (CMC) hydrogels.

[0068] First, each hydrogel system was immersed in simulated gastric fluid for 2 hours, and then weighed to obtain m0. Then, it was immersed in simulated gastric fluid for another 72 hours, and then weighed to obtain m1. The mass loss rate for this stage was calculated as (m0 - m1) / m0 * 100%. Next, the hydrogel system was placed in simulated intestinal fluid for 2 hours, and weighed to obtain m2. The mass loss rate for this stage was calculated as (m1 - m2) / m1 * 100%. The results are shown in Tables 4 and 5.

[0069] Table 4. Mass (g) of the hydrogel system at each stage

[0070] Table 5 Mass loss rate of hydrogel system

[0071] In the acidic environment of the stomach: the system remained in a stable swollen state for 72 hours, with a mass loss rate of less than 5% after 72 hours, proving its excellent stability in gastric juice. Under the same conditions, the mass loss rate of CMC hydrogel reached 27.4%.

[0072] Intestinal neutral environment: In the example, the hydrogel triggered rapid dehydration of the core layer in simulated intestinal fluid, and the system volume decreased to about 30% of the original swollen volume within 2 hours. This rapid response mechanism ensured the timely expulsion of the system from the intestine. In contrast, Comparative Example 1 and CMC hydrogels showed almost no significant mass loss.

[0073] Experiment Example 4 This experimental example uses the hydrogel system prepared in Example 1 to verify the gastric retention effect.

[0074] Verification method for gastric retention effect: The hydrogel system prepared in Example 1 was placed into the stomach of Bama pigs using a gastroscope. Immediately after the injection of purified water (500 mL), the expansion state of the hydrogel system in the stomach of the Bama pigs was observed. The state of the hydrogel in the stomach was observed again using a gastroscope after 72 hours. The state diagram of the hydrogel system after water injection into the stomach of the Bama pigs is shown below. Figure 5 The state of the hydrogel system in the stomach of Bama pigs after 72 hours is shown in the figure. Figure 6 .

[0075] Combination Figure 1 and Figure 2It can be seen that the hydrogel can fully expand within 30 minutes after being placed in the stomach and can still maintain its structural integrity after 72 hours.

[0076] In summary, the hydrogel system provided by the embodiments of the present invention has excellent swelling performance, and can rapidly swell to more than 100 times its original volume in a short time, thus prolonging its residence time in the body; the swelling rate can be adjusted by adjusting the particle size of the water-absorbing polymer, and the final volume can be adjusted by adjusting the amount of water-absorbing polymer in the capsule.

[0077] The hydrogel system has the following characteristics: good mechanical properties, which can withstand gastric mechanical peristalsis for a long time; strong environmental responsiveness and high stability, which can achieve controlled dehydration or degradation under specific environmental stimuli (such as the alkaline environment of the intestine (pH≥6.8)) and maintain structural integrity under acidic conditions in the stomach; pore control, which allows gastric juice to permeate through the porous structure (pore size 50-200μm) while preventing structural disintegration; and high biosafety, providing a feasible strategy for clinical application.

[0078] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A hydrogel system, characterized in that, The hydrogel system has a core-shell structure, comprising a core expansion layer, a stabilizing protective layer, and an intestinal fluid responsive layer from the inside out. The hydrogel system, after swelling for 10 minutes in an environment with a pH of 1.0-1.3, has a volume greater than 50 times its initial volume.

2. The hydrogel system according to claim 1, characterized in that, The core expansion layer comprises a water-absorbing polymer and a pore-forming agent in a mass ratio of (1-5):1; And / or, the porosity of the core expansion layer is 82.6%-88%.

3. The hydrogel system according to claim 2, characterized in that, The water-absorbing polymer is selected from at least one of sodium polyacrylate, polyacrylamide, polyvinyl alcohol, starch-acrylic acid graft copolymer, sodium polystyrene sulfonate, and carboxymethyl cellulose; Preferably, the particle size of the water-absorbing polymer is 100μm-150μm; And / or, the pore-forming agent is selected from at least one of konjac glucomannan, xanthan gum, guar gum, sodium alginate, chitosan and carrageenan.

4. The hydrogel system according to claim 1, characterized in that, The stabilizing protective layer is composed of a pH-sensitive composite hydrogel; Preferably, the stabilizing protective layer comprises chitosan, polyacrylate, and gel polysaccharide in a mass ratio of (2-5):(1-3):

1.

5. The hydrogel system according to claim 1, characterized in that, The intestinal fluid response layer comprises polyvinyl alcohol and 3,4-dihydroxyphenylalanine in a mass ratio of 1:(3-8).

6. A method for preparing a hydrogel system according to any one of claims 1-5, characterized in that, Includes the following steps: After mixing the water-absorbing polymer and the pore-forming agent in a certain proportion, the mixture is reacted at a temperature of 65℃-75℃ for 1.5h-2.5h, and then freeze-dried at a temperature of -45℃ to -55℃ for 20h-25h to obtain the core expansion layer material. Chitosan, polyacrylate and gel polysaccharide are mixed in proportion and reacted at pH 3.5-4.5 for 3.5-4.5 hours to obtain a stable protective layer material. Polyvinyl alcohol and 3,4-dihydroxyphenylalanine were mixed in a certain proportion and reacted at pH 7.0-7.5 for 1-12 hours to obtain the intestinal fluid responsive layer material. After assembling the core expansion layer material, the stable protective layer material, and the intestinal fluid response layer material, the hydrogel system is obtained by freeze-drying at a temperature of -45°C to -55°C for 45-55 hours.

7. The preparation method according to claim 6, characterized in that, When preparing the core expansion layer material, a suspension of 18% (w / v)-25% (w / v) is obtained by mixing the water-absorbing polymer and the pore-forming agent. And / or, when preparing the stable protective layer material, chitosan, polyacrylate and gel polysaccharide are mixed in solution form respectively; The chitosan solution includes 1.2% (w / v)-2.5% (w / v) chitosan acetate solution, the polyacrylate solution includes 3% (w / v)-8% (w / v) polyacrylate aqueous solution, and the gel polysaccharide solution includes 1% (w / v)-5% (w / v) gel polysaccharide aqueous solution. Preferably, the gel polysaccharide solution is prepared under water bath conditions at a temperature of 85℃-95℃; And / or, when preparing the intestinal fluid responsive layer material, polyvinyl alcohol is added in the form of a solution, the polyvinyl alcohol solution comprising 8% (w / v) to 12% (w / v) of an aqueous solution of polyvinyl alcohol.

8. The preparation method according to claim 6, characterized in that, The assembly process for preparing the hydrogel system includes the following steps: The core expansion layer material is placed in the center of the mold of the stabilizing protective layer, the stabilizing protective layer material is injected and gelled; after the gelled stabilizing protective layer is coated with an intestinal fluid response layer solution, it is freeze-dried.

9. A gastric retention system, characterized in that, This includes the hydrogel system as described in any one of claims 1-5 or the hydrogel system prepared by the preparation method as described in claims 6-8.

10. The gastric retention system according to claim 9, characterized in that, The gastric retention system includes a hydrogel system having at least one of the following application methods: Method 1: The hydrogel system, after being soaked in an environment with a pH of 1.2-3.0 for 72 hours, exhibits a compressive strength ≥ 92.3% of the initial compressive strength and an elastic modulus ≥ 89.8% of the initial elastic modulus. Method 2: The mass loss rate of the hydrogel system after immersion in an environment with a pH of 1.2-3.0 for 24 hours is ≤5.2%; Method 3: The hydrogel system begins to dissolve in an environment with a pH of 6.8-7.4 within ≤15 minutes; Method 4: The volume of the hydrogel system decreased by more than 20% after swelling treatment in an environment with pH 6.8-7.4 for 2 hours.

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