Injectable hydrogel for gastric filling, method for preparing same, and use thereof

Abstract

Disclosed are an injectable hydrogel for gastric filling, a method for preparing same, and use thereof, wherein the injectable hydrogel comprises a first cross-linked network and a second cross-linked network that interpenetrate each other. The first cross-linked network is formed by mixing and cross-linking a polysaccharide salt with a divalent cation, and the second cross-linked network is formed by mixing and cross-linking an oxidized polysaccharide salt with an amino material. The method comprises preparing a polysaccharide salt solution, preparing an auxiliary agent solution, and mixing the polysaccharide salt solution with the auxiliary agent solution to prepare the hydrogel. The preparation of the auxiliary agent solution comprises separately preparing a divalent cation solution, an oxidation solution, and an amino cross-linking solution. The hydrogel prepared by the preparation method exhibits both shear-thinning performance and mechanical stability.

Description

Injectable hydrogel for gastric filling and its preparation method and application Technical Field

[0001] The present invention relates to the technical field of medical hydrogels, in particular to an injectable hydrogel for gastric filling, a preparation method and an application thereof. Background Art

[0002] Endoscopic minimally invasive surgery is a procedure performed using modern medical devices and related equipment such as laparoscopes and gastroenteroscopes. Unlike traditional surgical procedures, endoscopic minimally invasive surgery does not require incision and can reduce damage to the human body compared to traditional surgical procedures. It has the advantages of less trauma, less pain, and faster recovery. However, in current clinical surgical procedures, because the diseased tissue is wrapped by the surrounding connective tissue, even if endoscopic minimally invasive surgery is used to separate the diseased tissue, complications such as bleeding and perforation are prone to occur. This is especially true in complex surgeries, which require a combination of sharp mechanical separation and blunt separation with high-frequency electrosurgical surgery. This results in long operative times, a high risk of bleeding, and greater surgical difficulty.

[0003] The submucosal injection of conventional mucosal injection is widely used in the clinic, and the submucosal injection of conventional mucosal injection is widely used in the clinic. And good submucosal injection can form submucosal liquid pad in vivo, makes the lesion site fully bulge, and then can effectively prevent and reduce the complication of operation, reduce surgical risk. Wherein, isotonic saline is the most widely used submucosal injection in current clinical practice, and its advantage is that it is cheap, isotonic and non-toxic, and its shortcoming is then to be rapidly absorbed by surrounding tissue, and submucosal liquid pad is thin and holding time is short, needs to be repeatedly injected in a large number during surgical operation. The submucosal injection of current clinical research (such as hypertonic saline, hypertonic glucose, hydroxypropyl methylcellulose, sodium hyaluronate, autologous blood, fibrinogen etc.) is all more or less subject to the restrictions such as biocompatibility, safety, holding time, and application effect is not good.

[0004] Hydrogels are polymer materials with three-dimensional network structures. They possess excellent stability, high water content, and a cytoplasmic matrix-like structure and properties. They offer advantages such as minimally invasive transplantation, filling irregular wounds, and encapsulating cells, drugs, and bioactive molecules. They have garnered widespread attention in areas such as tissue repair and drug delivery. Injectable hydrogels, which can be minimally invasively injected into the body and swell into a gel at specific locations, are a preferred material for submucosal fillers.

[0005] Existing injectable hydrogels can be divided into two categories based on the site of gelation. One category is to inject the gelling material into the human body and then slowly gel in situ in the human body, referred to as in situ gelling hydrogels; the other category is to use the principle of shear thinning to make the hydrogel gel in vitro and then inject it into the human body through a syringe. The shear force during the injection process will make the gel thinner and enhance its fluidity for easy injection. When the gel enters the human body and loses the shear force, the gel will be restored and cross-linked and solidified again, referred to as shear thinning hydrogels. However, both types of hydrogels have certain disadvantages. Although in situ gelling hydrogels are simple to operate and the gel has certain mechanical properties, their gelation speed and time are difficult to control. If the gelation is too fast, it is easy to clog the syringe, and if the gelation is too slow, it will delay the operation time and increase the risk of surgery, and there are problems such as slow degradation. Although shear thinning hydrogels can solve the problem of difficult control of gelation time, because their cross-linking effect is dynamically reversible, their mechanical properties and stability are often poor.

[0006] Summary of the Invention

[0007] To overcome the above shortcomings, the purpose of the present invention is to provide an injectable hydrogel for gastric filling, a preparation method and application thereof, and to construct a hydrogel with a double network structure so that the hydrogel can have both shear thinning properties and mechanical stability properties.

[0008] In order to achieve the above objectives, one of the technical solutions adopted by the present invention is: an injectable hydrogel for gastric filling, comprising a first layer cross-linked network and a second layer cross-linked network interlaced with each other, the first layer cross-linked network being cross-linked by polysaccharide salt and divalent cations, and the second layer cross-linked network being cross-linked by oxidized polysaccharide salt and amino material.

[0009] By cross-linking polysaccharide salts with divalent cations to form a first-layer cross-linked network with in-situ gelling properties, and then by oxidizing polysaccharide salts and cross-linking with amino materials to form a second-layer cross-linked network with shear-thinning properties, the final injectable hydrogel can have both shear-thinning properties and mechanical stability. The mutual interpenetration of the first-layer cross-linked network and the second-layer cross-linked network strengthens the interaction between the two, further improving the mechanical properties of the injectable hydrogel.

[0010] Furthermore, the injectable hydrogel also includes a dispersant, which includes at least one of magnesium aluminum silicate and lithium magnesium silicate. The dispersant (nanometal silicate) can further enhance the mechanical properties and stability of the injectable hydrogel by utilizing its physical electrostatic effect. Nanometal silicates also exhibit certain pharmaceutical activity and can accelerate the degradation of metal and silicon ions under gastric acid conditions, thereby promoting cell proliferation, wound healing, and angiogenesis. Furthermore, nanometal silicates have a large surface area and surface energy, which can increase the contact area with bacteria. When used in combination with antimicrobial agents, they can enhance the antibacterial effect.

[0011] The second technical solution adopted by the present invention is: a method for preparing an injectable hydrogel for gastric filling, comprising preparing a polysaccharide salt solution, preparing an adjuvant solution, and mixing the polysaccharide salt solution and the adjuvant solution to prepare the injectable hydrogel; wherein, preparing the adjuvant solution comprises preparing a divalent cation solution, an oxidizing solution, and an amino cross-linking solution.

[0012] When an auxiliary agent solution containing a divalent cation solution, an oxidizing solution, and an amino cross-linking solution is mixed with a polysaccharide salt solution, part of the polysaccharide salt can mix with the divalent cations to form a first-layer cross-linked network with in-situ gelling properties. Through cross-linking, the polymer chains are tightly bound, and the cross-linking synergistic effect between the polymer chains and the metal cations is fully exerted to improve the mechanical properties and stability of the hydrogel; at the same time, part of the polysaccharide salt can be oxidized by the oxidizing solution and undergo a Schiff base reaction with the amino cross-linking solution to form a second-layer cross-linked network with shear thinning properties.

[0013] Furthermore, the mixing preparation of the injectable hydrogel includes: partially oxidizing the polysaccharide salt solution with an oxidizing solution to obtain an oxidized polysaccharide salt solution; and mixing the oxidized polysaccharide salt solution, a divalent cation solution, and an amino cross-linking solution to obtain the injectable hydrogel.

[0014] First, the polysaccharide salt solution is partially oxidized using an oxidizing solution, so that only a portion of the polysaccharide salt in the polysaccharide salt solution is oxidized to oxidized polysaccharide salt. This means that the oxidized polysaccharide salt solution contains both unoxidized and oxidized polysaccharide salts. When the oxidized polysaccharide salt solution is mixed with a divalent cation solution and an amino cross-linking solution, the divalent cations cross-link with the polysaccharide salt to form a first-layer cross-linked network with in-situ gelling properties, while the oxidized polysaccharide salt undergoes a Schiff base reaction with the amino-containing substances in the amino cross-linking solution to form a second-layer cross-linked network with shear-thinning properties. The combined effect of the first and second cross-linked networks promotes close interpenetration and interaction between macromolecular chains, thereby improving material strength, cross-linking rate, and cross-linking material utilization.

[0015] In practical applications, the amount of oxidized polysaccharide in the polysaccharide solution can be controlled by controlling the amount and concentration of the oxidizing solution added, which in turn helps to regulate the gelation speed and ratio of the first-layer cross-linked network and the second-layer cross-linked network, thereby improving the mechanical properties of the hydrogel and controlling the gelation time.

[0016] In addition, the Schiff base reaction of the second-layer cross-linked network is pH-responsive, which enables the hydrogel to have good drug release and biodegradability. During surgery, because the stomach is in an empty state (pH>6), the hydrogel can present a gel state with good mechanical properties and adhesion; after surgery, the stomach secretes gastric acid to form an acidic environment (pH<6), and the hydrogel will decrosslink and become a sol state. At this time, the drug encapsulated in the hydrogel can be released in large quantities, and the hydrogel is also easier to be excreted from the body. When the hydrogel is loaded with drugs, the drug can be mixed in a divalent cation solution and then mixed with other solutions to prepare an injectable hydrogel.

[0017] Furthermore, preparing the auxiliary agent solution also includes preparing a dispersant; and mixing to prepare the injectable hydrogel includes: partially oxidizing the polysaccharide salt solution with an oxidizing solution to obtain an oxidized polysaccharide salt solution; and mixing the oxidized polysaccharide salt solution, a divalent cation solution, an amino crosslinking solution, and a dispersant to produce the injectable hydrogel. Furthermore, the dispersant is a nano-metal silicate.

[0018] Furthermore, the dispersant is pre-dispersed in the divalent cation solution and then mixed with other solutions.

[0019] The addition of a dispersant can effectively improve the final rheological properties of the hydrogel, not only enhancing shear-thinning properties but also, when nano-metal silicates are used as dispersants, further enhancing the hydrogel's mechanical strength and stability through their electrostatic effects. Nano-metal silicates also possess certain pharmaceutical activity, accelerating the degradation of metal and silicon ions under gastric acid conditions, thereby promoting cell proliferation, wound healing, and angiogenesis. Furthermore, nano-metal silicates have a large surface area and surface energy, increasing their contact area with bacteria. When used in combination with antimicrobial agents, they can enhance their antibacterial effects.

[0020] Furthermore, preparing the oxidizing solution includes: adding an oxidant to deionized water and stirring until the oxidant is completely dissolved; wherein the mass ratio of the oxidant to the deionized water is 1:10-20.

[0021] By controlling the mass ratio of the oxidant to deionized water to control the concentration of the oxidizing solution, and by controlling the mass ratio of the oxidant to the polysaccharide salt to control the oxidation process of the polysaccharide salt, the polysaccharide salt solution can be directly mixed with the oxidizing solution when the polysaccharide salt is oxidized in the first step. Since the amount of the oxidant added is controllable, it is possible to control the polysaccharide salt solution so that only part of the polysaccharide salt can be oxidized, while part of the polysaccharide salt remains unoxidized. In this way, when other auxiliary agents are mixed in the second step, the oxidized polysaccharide salt can form a second layer of cross-linked network with the amino cross-linking solution, and the unoxidized polysaccharide salt forms a first layer of cross-linked network with the divalent cation solution.

[0022] Specifically, the oxidizing agent is periodate, and the periodate can be sodium periodate.

[0023] Furthermore, preparing the amino cross-linking solution includes: adding the amino material to deionized water and stirring until the amino material is completely dissolved; wherein the mass ratio of the amino material to the deionized water is 1:30-100.

[0024] Furthermore, the amino material is at least one of peramino-β-cyclodextrin (β-CD-(NH2)7), gelatin, and chitosan.

[0025] Specifically, partially oxidizing the polysaccharide salt solution with the oxidizing solution includes injecting the polysaccharide salt solution and the oxidizing solution into a mold according to a predetermined ratio, allowing the mixture to react, and then adding ethylene glycol to terminate the reaction. Furthermore, the predetermined ratio is such that the mass ratio of the oxidizing agent in the oxidizing solution to the polysaccharide salt in the polysaccharide salt solution is 1:2-5.

[0026] Furthermore, the set ratio is that the mass ratio of the oxidant contained in the oxidation solution to the polysaccharide salt in the polysaccharide salt solution is 1:2-4.

[0027] The reaction time also determines the degree of oxidation. Generally speaking, the reaction time can be controlled at around 24 hours, and the reaction is basically complete when it reaches 24 hours. Of course, different reaction times can be set according to specific needs.

[0028] Furthermore, after ethylene glycol is added to terminate the reaction, a divalent cation solution, an amino cross-linking solution, and a dispersant are added in specific ratios.

[0029] Furthermore, the volume ratio of the oxidized polysaccharide salt solution to the divalent cation solution is 1 to 10:1, and the volume ratio of the oxidized polysaccharide salt solution to the amino cross-linking solution is 1 to 10:1.

[0030] Specifically, preparing the dispersant includes weighing an appropriate amount of a pharmacologically active dispersant, wherein the pharmacologically active dispersant comprises 2-5% by weight of the injectable hydrogel. The pharmacologically active dispersant comprises at least one of magnesium aluminum silicate and lithium magnesium silicate. Using magnesium aluminum silicate or lithium magnesium silicate as a dispersant accelerates the degradation of magnesium and silicon ions under gastric acidity. Magnesium ions promote cell proliferation and wound healing, while silicon ions promote angiogenesis.

[0031] Furthermore, preparing the divalent cation solution includes: adding a divalent metal salt to deionized water at a mass ratio of 1:100 to 1200, and stirring until the divalent metal salt is completely dissolved.

[0032] Furthermore, the mass ratio of the divalent metal salt to the deionized water is 1:120-500.

[0033] Divalent metal salts are usually calcium salts (such as calcium gluconate and calcium sulfate). Since the G unit in polysaccharide salts (alginate) easily reacts with divalent metal ions, and different divalent metal ions have different affinities for polysaccharide salts, and divalent calcium ions have the best cross-linking properties, divalent calcium ions are often used in the field of biomedicine.

[0034] Furthermore, preparing the polysaccharide salt solution includes: adding the polysaccharide salt to deionized water at a mass ratio of 1:80 to 1200, and stirring until the polysaccharide salt is completely dissolved.

[0035] Furthermore, the mass ratio of the polysaccharide salt to deionized water is 1:120-600.

[0036] Furthermore, the polysaccharide salt includes at least one of sodium alginate, potassium alginate, and lithium alginate.

[0037] The third technical solution adopted by the present invention is: an application of the above-mentioned injectable hydrogel for gastric filling in gastric surgical filling.

[0038] The beneficial effects of the present invention are:

[0039] (1) By combining in situ gelation and shear thinning, a double-network hydrogel was constructed, which not only has the injectable property of shear thinning, but also compensates for the lack of mechanical stability of a single-network hydrogel through double-network cross-linking.

[0040] (2) The gelation speed and time of hydrogel can be controlled by adjusting the ratio and concentration of each material.

[0041] (3) When forming the second layer of cross-linked network, the Schiff base reaction was used to add pH response function, making the hydrogel easier to degrade in the gastric acid environment in the stomach after surgery, thereby improving the problem of difficult degradation of alginate gel and making it more biodegradable and safe.

[0042] (4) By using nano-metal silicates as dispersants, the shear thinning and mechanical properties of the gel are further enhanced under the pre-activation of the monovalent cations contained in the gel (i.e., sodium ions, potassium ions, and lithium ions in polysaccharide salts and periodates). At the same time, the pharmacological activity of nano-metal silicates is utilized to promote wound healing, angiogenesis, and resist excessive gastric acid. DETAILED DESCRIPTION

[0043] The preferred embodiments of the present invention are described in detail below so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more precise definition of the protection scope of the present invention.

[0044] Example

[0045] The injectable hydrogel for gastric filling of the present invention comprises a first cross-linked network and a second cross-linked network interpenetrating each other, wherein the first cross-linked network is formed by cross-linking polysaccharide and divalent cations, and the second cross-linked network is formed by cross-linking oxidized polysaccharide and amino materials.

[0046] By mixing and cross-linking polysaccharide salts with divalent cations to form a first-layer cross-linked network with in-situ gelling properties, and then by mixing and cross-linking oxidized polysaccharide salts with amino materials to form a second-layer cross-linked network with shear-thinning properties, the final injectable hydrogel can have both shear-thinning properties and mechanical stability. The mutual interpenetration of the first-layer cross-linked network and the second-layer cross-linked network strengthens the interaction between the two, further improving the mechanical properties of the injectable hydrogel.

[0047] Furthermore, the injectable hydrogel also includes a dispersant comprising at least one of magnesium aluminum silicate and lithium magnesium silicate. Metal silicates can further enhance the mechanical properties and stability of the injectable hydrogel through their physical electrostatic effects. Nano-metal silicates also possess certain pharmaceutical activity, accelerating the degradation of metal and silicon ions under gastric acid conditions, thereby promoting cell proliferation, wound healing, and angiogenesis. Furthermore, nano-metal silicates have a large surface area and surface energy, increasing their contact area with bacteria. When used in combination with antimicrobial agents, they can enhance their antibacterial effects.

[0048] The present invention also provides a method for preparing an injectable hydrogel for gastric filling, comprising the following steps:

[0049] (1) preparing a polysaccharide salt solution;

[0050] (2) preparing an auxiliary agent solution, including separately preparing a divalent cation solution, an oxidizing solution, an amino cross-linking solution, and a dispersant;

[0051] (3) The polysaccharide salt solution and the adjuvant solution are mixed to prepare an injectable hydrogel.

[0052] Specifically, the preparation of the polysaccharide salt solution includes: adding the polysaccharide salt to deionized water, the mass ratio of the polysaccharide salt to deionized water is 1:80~1200, and then placing it in a heated magnetic stirrer, stirring vigorously at a temperature of 40~50°C (stirring rate of about 1000r / min) for 1~2 hours until the polysaccharide salt is completely dissolved to obtain a polysaccharide salt solution. Exemplarily, the polysaccharide salt includes at least one of sodium alginate, potassium alginate, and lithium alginate. Furthermore, the mass ratio of the polysaccharide salt to deionized water is preferably 1:120~600.

[0053] The divalent cation solution is prepared by adding a divalent metal salt to deionized water at a mass ratio of 1:100 to 1200, then vigorously stirring the mixture in a heated magnetic stirrer at 40°C to 50°C for 1 to 5 hours until the divalent metal salt is completely dissolved, thereby obtaining the divalent metal cation solution. Exemplarily, the divalent metal salt includes at least one of calcium gluconate and calcium sulfate. Furthermore, the mass ratio of the divalent metal salt to deionized water is preferably 1:120 to 500.

[0054] The oxidizing solution is prepared by adding periodate to deionized water in a mass ratio of periodate to deionized water of 1:10-20, and then vigorously stirring at 1000 rpm until the periodate is completely dissolved, thereby obtaining the oxidizing solution. The mass ratio of periodate to the polysaccharide in the polysaccharide solution is 1:2-5. Exemplarily, the periodate comprises sodium periodate.

[0055] The amino cross-linking solution is prepared by adding an amino material to deionized water at a mass ratio of 1:30 to 100, and then stirring at room temperature until completely dissolved, thereby obtaining the amino cross-linking solution. Exemplarily, the amino material includes at least one of peramino-β-cyclodextrin (β-CD-(NH2)7), gelatin, and chitosan.

[0056] The dispersant is prepared by weighing an appropriate amount of a pharmacologically active dispersant such that the pharmacologically active dispersant accounts for 2-5% of the mass of the injectable hydrogel. For example, the pharmacologically active dispersant comprises at least one of magnesium aluminum silicate and lithium magnesium silicate.

[0057] It should be noted that the preparation of polysaccharide salt solution and auxiliary agent solution (including divalent cation solution, oxidizing solution, amino cross-linking solution, and pharmacologically active dispersant) are all preparation stages of the gel raw materials. Therefore, the order of preparation is not limited.

[0058] In some embodiments, when mixing the polysaccharide salt solution and the adjuvant solution, the polysaccharide salt solution is first partially oxidized using an oxidizing solution to obtain an oxidized polysaccharide salt solution; the oxidized polysaccharide salt solution, the divalent cation solution, the amino cross-linking solution, and the dispersant are mixed to prepare an injectable hydrogel.

[0059] Specifically, different syringes are used to draw the polysaccharide salt solution and the oxidation solution, and the polysaccharide salt in the polysaccharide salt solution is injected into the mold at a mass ratio of 1:2 to 5 (preferably 1:2 to 4) according to the oxidant (periodate) contained in the oxidation solution and the polysaccharide salt in the polysaccharide salt solution. After standing for 24 hours, ethylene glycol is added to terminate the reaction to obtain an oxidized polysaccharide salt solution; after 15 minutes, the reaction is terminated, and a divalent cation solution (pharmacologically active dispersant is pre-dispersed in the divalent cation solution) and an amino cross-linking solution are added, quickly and evenly mixed, and after standing for 1 to 60 minutes, an injectable hydrogel is obtained. Furthermore, the volume ratio of the oxidized polysaccharide salt solution, the divalent cation solution, and the amino cross-linking solution is 1 to 10:1:1.

[0060] When oxidizing the polysaccharide salt, the amount of polysaccharide salt participating in the oxidation reaction in the polysaccharide salt solution can be controlled by controlling the volume ratio of the polysaccharide salt solution to the oxidation solution, so that only a portion of the polysaccharide salt in the polysaccharide salt solution is oxidized; and then, when the divalent cation solution, the amino cross-linking solution, and the pharmacologically active dispersant are subsequently mixed, the oxidized polysaccharide salt can form a second layer of cross-linking network with the amino cross-linking solution, while the unoxidized polysaccharide salt forms a first layer of cross-linking network with the divalent cation solution.

[0061] The injectable hydrogel prepared according to the above scheme can gel within 3 to 10 minutes after mixing, which can meet the injection operation time requirement during surgery.

[0062] Example 1

[0063] (1) Preparation of polysaccharide salt solution: Add 3 g of sodium alginate to 500 ml of deionized water and stir until the sodium alginate is completely dissolved to obtain a sodium alginate solution;

[0064] (2) Preparation of auxiliary agent solution:

[0065] Add 2.5 g of calcium gluconate to 500 ml of deionized water and stir until the calcium gluconate is completely dissolved to obtain a calcium gluconate solution;

[0066] Add 10 g of sodium periodate to 200 ml of deionized water and stir until the sodium periodate is completely dissolved to obtain a sodium periodate solution;

[0067] Add 5 g of peramino-β-cyclodextrin to 300 ml of deionized water and stir until the peramino-β-cyclodextrin is completely dissolved to obtain an amino cross-linking solution;

[0068] (3) 100 ml of sodium alginate solution and 3 ml of sodium periodate solution (wherein the mass ratio of sodium periodate to sodium alginate is 1:4) were drawn into the mold using different syringes respectively, and injected into the mold at the same time. After reacting for 24 h at room temperature (25°C) in the dark, 0.6 ml of ethylene glycol was added. The reaction was terminated after 15 minutes to obtain an oxidized polysaccharide acid salt solution. Then, calcium gluconate solution and amino cross-linking solution were injected into the mold using different syringes. The volume ratio of calcium gluconate solution, amino cross-linking solution and oxidized sodium alginate solution was 1:1:4. They were quickly mixed and allowed to stand to obtain a hydrogel.

[0069] Example 2

[0070] (1) Preparation of polysaccharide salt solution: Add 1 g of sodium alginate to 500 ml of deionized water and stir until the sodium alginate is completely dissolved to obtain a sodium alginate solution;

[0071] (2) Preparation of auxiliary agent solution:

[0072] Add 4 g of calcium gluconate to 500 ml of deionized water and stir until the calcium gluconate is completely dissolved to obtain a calcium gluconate solution;

[0073] Add 20 g of sodium periodate to 200 ml of deionized water and stir until the sodium periodate is completely dissolved to obtain a lithium periodate solution;

[0074] Add 9 g of peramino-β-cyclodextrin to 300 ml of deionized water and stir until the peramino-β-cyclodextrin is completely dissolved to obtain an amino cross-linking solution;

[0075] (3) Use different syringes to draw 100 ml of sodium alginate solution and 1 ml of sodium periodate solution (the mass ratio of lithium periodate to sodium alginate is 1:2) respectively, and inject them into the mold at the same time. After reacting in the dark at room temperature (25°C) for 24 hours, add 0.4 ml of ethylene glycol. The reaction is terminated after 15 minutes to obtain an oxidized polysaccharide acid salt solution; then use different syringes to inject calcium gluconate solution and amino cross-linking solution into the mold. The volume ratio of calcium gluconate solution, amino cross-linking solution and oxidized sodium alginate solution is 1:1:6. Mix them quickly and evenly, and then let it stand to obtain a hydrogel.

[0076] Example 3

[0077] (1) Preparation of polysaccharide salt solution: Add 4 g of sodium alginate to 500 ml of deionized water and stir until the sodium alginate is completely dissolved to obtain a sodium alginate solution;

[0078] (2) Preparation of auxiliary agent solution:

[0079] Add 1.5 g of calcium gluconate to 500 ml of deionized water and stir until the calcium gluconate is completely dissolved to obtain a calcium gluconate solution;

[0080] Add 15 g of sodium periodate to 200 ml of deionized water and stir until the sodium periodate is completely dissolved to obtain a sodium periodate solution;

[0081] Add 6 g of peramino-β-cyclodextrin to 300 ml of deionized water and stir until the peramino-β-cyclodextrin is completely dissolved to obtain an amino cross-linking solution;

[0082] (3) 100 ml of sodium alginate solution and 4 ml of sodium periodate solution (the mass ratio of sodium periodate to sodium alginate is 1:2.67) were drawn into the mold using different syringes respectively. The solution was then injected into the mold at the same time. After reacting for 24 h in the dark at room temperature (25°C), 1.2 ml of ethylene glycol was added. The reaction was terminated after 15 min to obtain an oxidized polysaccharide acid salt solution. Calcium gluconate solution and amino cross-linking solution were then injected into the mold using different syringes. The volume ratio of calcium gluconate solution, amino cross-linking solution and oxidized sodium alginate solution was 1:1:2. The mixture was quickly mixed and allowed to stand to obtain a hydrogel.

[0083] Example 4

[0084] This embodiment is basically the same as embodiment 1, except that: in step (3) of this embodiment, the sodium alginate solution used is 100 ml, and the sodium periodate solution is 2.4 ml (wherein the mass ratio of sodium periodate to sodium alginate is 1:5).

[0085] Example 5

[0086] This embodiment is basically the same as Example 1, except that: the preparation auxiliary agent solution of this embodiment further includes 4g of nano-lithium magnesium silicate, and the nano-lithium magnesium silicate is pre-dispersed in the calcium gluconate solution; step (3) is: using different syringes to draw 100ml of sodium alginate solution and 3ml of sodium periodate solution (wherein the mass ratio of sodium periodate to sodium alginate is 1:4), and injecting them into the mold at the same time, reacting at room temperature (25°C) in the dark for 24h, adding 0.6ml of ethylene glycol, and terminating the reaction after 15min to obtain an oxidized polysaccharide salt solution; then using different syringes to inject the calcium gluconate solution and amino cross-linking solution dispersed with nano-lithium magnesium silicate into the mold, the volume ratio of the calcium gluconate solution, the amino cross-linking solution and the sodium alginate solution is 1:1:4, quickly mixing them evenly, and obtaining a hydrogel after standing.

[0087] Example 6

[0088] This embodiment is basically the same as embodiment 5, except that 7 g of nano-lithium magnesium silicate is used in this embodiment.

[0089] Comparative Example 1

[0090] (1) Preparation of polysaccharide salt solution: Add 3 g of sodium alginate to 500 ml of deionized water and stir until the sodium alginate is completely dissolved to obtain a sodium alginate solution;

[0091] (2) Preparation of auxiliary agent solution:

[0092] Add 2.5 g of calcium gluconate to 500 ml of deionized water and stir until the calcium gluconate is completely dissolved to obtain a calcium gluconate solution;

[0093] (3) Sodium alginate solution and calcium gluconate solution were drawn up using different syringes, and injected into the mold at the same time in a volume ratio of 4:1 between sodium alginate solution and calcium gluconate solution, mixed quickly and evenly, and allowed to stand to obtain a hydrogel.

[0094] Comparative Example 2

[0095] This comparative example is basically the same as Example 1, except that: in step (2) of this example, when preparing the auxiliary agent solution, the calcium gluconate solution is not prepared; accordingly, step (3) is: 100 ml of sodium alginate solution and 3 ml of sodium periodate solution (wherein the mass ratio of sodium periodate to sodium alginate is 1:4) are respectively drawn using different syringes, and injected into the mold at the same time. After reacting for 24 hours at room temperature (25°C) in the dark, 0.6 ml of ethylene glycol is added, and the reaction is terminated after 15 minutes to obtain an oxidized polysaccharide acid salt solution; then, the amino cross-linking solution is also injected into the mold using a syringe, and the volume ratio of the amino cross-linking solution to the oxidized sodium alginate solution is 1:4. The mixture is quickly mixed and allowed to stand to obtain a hydrogel.

[0096] Comparative Example 3

[0097] This comparative example is basically the same as Example 1, except that: in step (3) of this example, the sodium alginate solution used is 100 ml, and the sodium periodate solution is 12 ml (wherein the mass ratio of sodium periodate to sodium alginate is 1:1).

[0098] Comparative Example 4

[0099] This comparative example is basically the same as Example 7, except that the mass of the added nano-lithium magnesium silicate is 10 g.

[0100] The hydrogels of Examples 1 to 6 and Comparative Examples 1 to 4 were tested for mechanical properties and injection resistance. The test results are shown in Table 1. The test method is as follows:

[0101] Mechanical Properties: The hydrogel was formed into a cylindrical shape with a diameter of 7 mm and a height of 8.5 mm, and vaseline was evenly coated on the surface. The tensile strength of the hydrogel was then tested using a universal mechanical testing machine. The compressive strength of the hydrogel was also tested by compressing the hydrogel at a speed of 1 mm / min. When conducting mechanical property tests, 10 samples were generally tested for each example and comparative example, and the average value of the 10 samples was used as the corresponding tensile strength and compressive strength.

[0102] Injection resistance: Using an Adberg digital push-pull force gauge, the test head contacts a 5ml syringe and pushes the piston core rod to obtain a uniform thrust value displayed in N. The injection resistance tests the injection resistance of pure water and pre-gel mixture injected into the lower part of the pig's gastric mucosa. According to the national standard GB15810-2019 for disposable sterile syringes, the sliding capacity value of the syringe should meet the following requirements: when the nominal capacity of the syringe is less than 2ml, the maximum thrust is less than 10N; when the nominal capacity of the syringe is 2≤V<50ml, the maximum thrust should be less than 25N; when the nominal capacity of the syringe is greater than 50ml, the maximum thrust should be less than 30N.

[0103] Table 1 Performance test results of Examples 1 to 6 and Comparative Examples 1 to 4

[0104] Test result analysis

[0105] 1. Analysis of Examples 1-6 reveals that Examples 1-6 construct a bilayer crosslinked network with in-situ gelation and shear-thinning properties through the crosslinking of calcium gluconate, sodium periodate, and an amino crosslinking solution with alginate. Alginate chelates with calcium ions to form the first crosslinked network; oxidized alginate and the amino crosslinking solution form the second crosslinked network through dynamic, reversible imine bonds; and the bilayer crosslinked network is further reinforced by covalent crosslinking between the carboxyl and amino groups of the alginate, resulting in interpenetrating crosslinks. Consequently, the resulting hydrogel not only exhibits excellent mechanical properties and support, but also exhibits good injectability, requiring low injection force and making it suitable for physicians.

[0106] In addition, the hydrogels prepared in Examples 1-6 can exhibit a dynamic equilibrium state of gel-sol (the dynamic equilibrium transition pH value of gel-sol is 6). Taking Example 1 as an example, during the gelation process, the first layer of cross-linked network first cross-links to form a gel, and the gelation time is about 30 seconds. At this time, the mixed solution becomes thicker, while the second layer of cross-linked network gels more slowly, and the gelation time is about 3 to 5 minutes. At this time, the mixed solution officially becomes a hydrogel. Since the second layer of cross-linked network is a pH-sensitive Schiff base structure in a dynamic equilibrium state, its stability changes with the pH value of the external environment. When the pH value is less than 6, the imine bond composed of aldehyde and amino groups will be in an active state, easily broken, and unstable. At this time, the second layer of cross-linked network will degrade and become a sol state. When eating after surgery, the stomach secretes gastric acid, making it acidic (pH < 6). At this point, the material reacts, decrosslinking the gel material and transforming it into a sol state, which facilitates its degradation. (It is possible to encapsulate drugs in the gel material. During degradation, the drugs encapsulated in the gel can be released in large quantities, exhibiting excellent drug release properties, which is beneficial for drug administration and absorption.) Furthermore, in the sol state, the material is more easily excreted from the body, demonstrating good biodegradability, solving the problem of sodium alginate gel being difficult to degrade in the body.

[0107] 2. Analysis of Examples 1 and 4 shows that: Example 4, in which the amount of oxidant added is less than that of Example 1, exhibits decreased mechanical properties and increased injection resistance. This is because, when both networks are present and can interact synergistically, the degree of oxidation has a significant impact on the ratio of the two networks. As the amount of oxidant added increases, the degree of oxidation of the alginate increases, and the proportion of the second-layer cross-linked network formed by amino and aldehyde groups increases. The second-layer cross-linked network interacts more and more strongly with the first-layer cross-linked network of sodium alginate / calcium ions, resulting in the interpenetration and overlap of the two-layer networks, which can significantly enhance the mechanical properties of the gel. As for changes in injection resistance, since the second-layer cross-linked network is composed of dynamically reversible Schiff base bonds, it exhibits better shear thinning and injectability. Therefore, the greater the amount of oxidant added, the greater the degree of oxidation, and the greater the proportion of Schiff base structures, the better the injectability of the hydrogel, i.e., the lower the injection resistance.

[0108] 3. Analysis of Examples 1-4, 5-6, and Comparative Example 4 shows that compared to Examples 1-4, Examples 5-6 add nano-magnesium lithium silicate, and their shear-thinning properties and mechanical properties are changed. This may be because nano-magnesium lithium silicate helps to improve the shear-thinning properties of the gel, which can assist the hydrogel in being administered through a long endoscopic channel. At the same time, nano-magnesium lithium silicate can adsorb the polymer chains of the hydrogel, thereby forming giant physical cross-linking points, further enhancing the mechanical properties of the hydrogel. However, as the concentration of nano-magnesium lithium silicate increases, the viscosity of the hydrogel gradually increases, offsetting the excellent injectability brought about by partial shear thinning, thereby affecting the injection resistance. Therefore, the content of nano-magnesium lithium silicate needs to be controlled. When its content in the hydrogel is in the range of 2%-5%, the addition of nano-lithium magnesium silicate not only gives the hydrogel excellent mechanical support, but also exhibits good injectability, so that the hydrogel can be smoothly extruded from the needle; however, when the content of nano-lithium magnesium silicate is further increased, as shown in Comparative Example 4, its increased viscosity will affect the injectability, increase the injection resistance, and greatly increase the risk of clogging the syringe and causing inconvenience in surgical operation.

[0109] 4. Analysis of Example 1 and Comparative Example 1 reveals that, due to the absence of an amino cross-linking material in Comparative Example 1, no secondary network structure can be formed. The resulting gel network is a single-layer structure composed of calcium ions chelated with sodium alginate. Compared to Example 1, the gel in Comparative Example 1 exhibits inferior mechanical properties and strength. While it can be extruded smoothly from a syringe, its injectability is inferior to that of the gel containing a dynamic Schiff base, resulting in slightly higher injection resistance.

[0110] 5. Analysis of Example 1 and Comparative Examples 2-3 reveals that: Comparative Example 2 lacks calcium gluconate, thus failing to form a first-layer cross-linked network structure; while Comparative Example 3 incorporates an excess of the oxidizing agent sodium periodate, resulting in near-complete oxidation of the sodium alginate, leaving virtually no unoxidized sodium alginate available for chelation with the calcium gluconate to form a gel, and thus failing to form a first-layer cross-linked network structure. Compared to Example 1, Comparative Examples 2-3 fail to form a reinforced structure with alternating double-layer networks, resulting in inferior mechanical properties. However, due to the abundance of Schiff base structures formed by amino and aldehyde groups, Comparative Examples 2-3 exhibit excellent injectability, allowing the gel material to be extruded with minimal syringe force.

[0111] The above embodiments are only for illustrating the technical concept and features of the present invention. Its purpose is to enable people familiar with this technology to understand the content of the present invention and implement it. It cannot be used to limit the scope of protection of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of protection of the present invention.

Claims

1. An injectable hydrogel for gastric filling, characterized in that: The invention comprises a first cross-linked network and a second cross-linked network which are interlaced with each other. The first cross-linked network is cross-linked by polysaccharide acid salt and divalent cations, and the second cross-linked network is cross-linked by oxidized polysaccharide acid salt and amino material.

2. The injectable hydrogel for gastric filling according to claim 1, characterized in that: It also includes a dispersant, which includes at least one of magnesium aluminum silicate and magnesium lithium silicate.

3. A method for preparing an injectable hydrogel for gastric filling, characterized in that: The method comprises preparing a polysaccharide salt solution, preparing an auxiliary agent solution, and mixing the polysaccharide salt solution and the auxiliary agent solution to prepare an injectable hydrogel; wherein the preparing the auxiliary agent solution comprises preparing a divalent cation solution, an oxidation solution, and an amino cross-linking solution.

4. The preparation method according to claim 3, characterized in that: The mixing method for preparing the injectable hydrogel comprises: partially oxidizing the polysaccharide salt solution with an oxidizing solution to obtain an oxidized polysaccharide salt solution; and mixing the oxidized polysaccharide salt solution, a divalent cation solution, and an amino cross-linking solution to obtain the injectable hydrogel.

5. The preparation method according to claim 3, characterized in that: The preparation of the auxiliary agent solution also includes the preparation of a dispersant; the mixing to prepare the injectable hydrogel includes: partially oxidizing the polysaccharide acid salt solution with an oxidizing solution to obtain an oxidized polysaccharide acid salt solution; mixing the oxidized polysaccharide acid salt solution, a divalent cation solution, an amino cross-linking solution, and a dispersant to obtain an injectable hydrogel.

6. The preparation method according to claim 4 or 5, characterized in that: The volume ratio of the oxidized polysaccharide salt solution to the divalent cation solution is 1 to 10:1; the volume ratio of the oxidized polysaccharide salt solution to the amino cross-linking solution is 1 to 10:

1.

7. The preparation method according to claim 3, characterized in that: The preparation of the oxidizing solution comprises: adding an oxidant into deionized water and stirring until the oxidant is completely dissolved, wherein the mass ratio of the oxidant to the deionized water is 1:10-20; the preparation of the amino cross-linking solution comprises: adding an amino material into deionized water and stirring until the amino material is completely dissolved, wherein the mass ratio of the amino material to the deionized water is 1:30-100.

8. The preparation method according to claim 7, characterized in that: The oxidant is periodate; the amino material includes at least one of peramino-β-cyclodextrin, gelatin and chitosan.

9. The preparation method according to claim 4 or 5, characterized in that: The method of partially oxidizing the polysaccharide salt solution by using the oxidizing solution comprises injecting the polysaccharide salt solution and the oxidizing solution into the mold according to a set ratio, standing for reaction, and then adding ethylene glycol to terminate the reaction.

10. The preparation method according to claim 9, characterized in that: The set ratio is that the mass ratio of the oxidant contained in the oxidation solution to the polysaccharide salt in the polysaccharide salt solution is 1:2-5, preferably 1:2-4.

11. The preparation method according to claim 5, characterized in that: The preparation of the dispersant includes weighing an appropriate amount of a pharmacologically active dispersant for standby use; wherein the mass percentage of the pharmacologically active dispersant in the injectable hydrogel is 2-5%; and the pharmacologically active dispersant includes at least one of aluminum magnesium silicate and lithium magnesium silicate.

12. The preparation method according to claim 3, characterized in that: The preparation of the divalent cation solution comprises: adding a divalent metal salt to deionized water at a mass ratio of 1:100-1200, and stirring until the divalent metal salt is completely dissolved; the mass ratio of the divalent metal salt to deionized water is preferably 1:120-500.

13. The preparation method according to claim 3, characterized in that: The preparation of the polysaccharide salt solution comprises: adding the polysaccharide salt into deionized water at a mass ratio of 1:80-1200, and stirring until the polysaccharide salt is completely dissolved; the mass ratio of the polysaccharide salt to deionized water is preferably 1:120-600.

14. The preparation method according to claim 13, characterized in that: The polysaccharide salt includes at least one of sodium alginate, potassium alginate and lithium alginate.

15. Use of the injectable hydrogel for gastric filling according to claim 1 or 2 in gastric surgical filling.

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