Adhesive hydrogel and its preparation method and application

Abstract

The present invention belongs to the field of pharmaceutical preparations, and in particular to an adhesive hydrogel and its preparation method and application. The present invention adopts a mixed cross-linking system of PEGDA and a benzaldehyde-based polyethylene glycol derivative-polyamino polymer, which is solidified into a system in which two gels are evenly combined. After soaking in tannin, the adhesion performance of the hydrogel is greatly improved, and the adhesion strength can reach more than 20,000 Pa, and it shows good adhesion effect on a variety of materials. The present invention also uses covalent bonds to stably fix iodine-containing groups in the main chain of the hydrogel, so that the adhesive hydrogel also has a developing function, and long-term development is achieved while ensuring the developing effect, which can be used to guide radiotherapy positions, etc.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, in particular to the field under IPC classification number A61L24 / 04, and more specifically to an adhesive hydrogel and a preparation method and application thereof. Background Art

[0002] Hydrogels are polymer materials with a specific cross-linked network structure that exhibit excellent moisture retention, biocompatibility, and biodegradability. However, in wound dressings and surgical procedures, hydrogels typically lack adhesion, preventing them from adhering tightly to wounds and potentially causing them to fall off. To improve the suitability of existing gels for biomedical applications, many researchers are focusing on designing bioadhesive hydrogels with diverse properties.

[0003] Tannin is a polyphenolic substance extracted from plants. Thanks to its rich phenolic hydroxyl groups, tannin can form adhesion with various substances such as glass and metal by forming hydrogen bonds and coordination bonds. The latest research points out that after soaking tannin solution with PEGDA (polyethylene glycol diacrylate) hydrogel, the hydrogel becomes adhesive and can adhere to human tissues such as skin, heart, and bone (An All-in-One Tannic Acid-Containing Hydrogel Adhesive with High Toughness, Notch Insensitivity, Self-Healability, Tailorable TopograpHy, and Strong, Instant, and On-Demand Underwater Adhesion, "ACS Appl. Mater. Interfaces", 2021, Issue 13, Pages 9748-9761). However, the adhesion strength of tannin-polyethylene glycol hydrogels in the prior art is weak, or the scope of application is narrow, and they can only adhere between biological tissues.

[0004] Therefore, there is still a need to develop a biocompatible hydrogel with good adhesion and applicable to a variety of materials to meet a wide range of market needs. Summary of the Invention

[0005] In view of the defects of the prior art, the purpose of the present invention is to provide a method for preparing an adhesive hydrogel with strong adhesion, good biocompatibility, and degradability, which can adhere to the surfaces of various materials.

[0006] On the other hand, the present invention also aims to provide an adhesive hydrogel prepared by the above-mentioned method for preparing the adhesive hydrogel.

[0007] On the other hand, the present invention also aims to provide an application of the adhesive hydrogel prepared by the above-mentioned method for preparing the adhesive hydrogel.

[0008] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0009] A method for preparing an adhesive hydrogel comprises the following steps:

[0010] S1: preparing a PEGDA (polyethylene glycol diacrylate) solution and a polyethylene glycol derivative solution respectively, and mixing the PEGDA solution and the polyethylene glycol derivative solution to obtain solution A;

[0011] S2: Prepare a polyamino polymer solution, add a photocrosslinker, and adjust the pH to obtain solution B;

[0012] S3: Mixing solution A and solution B, irradiating with ultraviolet light for cross-linking reaction, and obtaining a gel;

[0013] S4: Soaking the gel obtained in step S3 in a tannin solution to obtain an adhesive hydrogel.

[0014] Preferably, the polyethylene glycol derivative is or;

[0015] Preferably, the number of arms of the benzaldehyde-terminated star-shaped multi-arm polyethylene glycol is 4 to 8, and examples thereof include 4 arms, 6 arms, or 8 arms;

[0016] Preferably, the number of arms of the iodobenzaldehyde-terminated star-shaped multi-arm polyethylene glycol is 4 to 8, and examples thereof include 4 arms, 6 arms, or 8 arms;

[0017] Preferably, the iodobenzaldehyde-terminated star-shaped multi-arm polyethylene glycol is prepared by the following method:

[0018] A star-shaped multi-arm polyethylene glycol, triiodobenzoic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (CAS No.: 25952-53-8) and DMAP are mixed, dissolved in dichloromethane, and stirred at room temperature for reaction; after the reaction is completed, p-formaldehyde benzoic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and DMAP are added to the reaction solution, and the reaction is continued by stirring at room temperature; after the reaction is completed, the solution is extracted with saturated brine / CH2Cl2 and concentrated, and the solution is precipitated with glacial ether three times and dried in vacuo to obtain a star-shaped multi-arm polyethylene glycol terminated with iodobenzaldehyde groups.

[0019] To enhance the imaging capabilities of bio-hydrogels, iodine-based developer can be used to functionalize the hydrogels. Conventional physical mixing methods, while simple to use, suffer from rapid diffusion of the developer, making it difficult to maintain imaging strength in vivo. This new method, by covalently linking iodine-containing groups to the hydrogel backbone, ensures uniform distribution of the developer within the hydrogel system and prevents loss of the developer, achieving long-lasting imaging while maintaining effective imaging results.

[0020] Preferably, the star-shaped multi-arm polyethylene glycol and benzaldehyde-terminated star-shaped multi-arm polyethylene glycol are purchased from Beijing Jiankai Technology Co., Ltd.

[0021] Preferably, the PEGDA is PEGDA (700) purchased from Adamas Life Company;

[0022] Preferably, the solvent of the PEGDA solution, tannin solution, and polyamino polymer solution is water;

[0023] Preferably, the solvent of the polyethylene glycol derivative solution is 0.02M phosphate buffer;

[0024] Further preferably, the pH of the 0.02M phosphate buffer is 4;

[0025] Preferably, the mass ratio of PEGDA to polyethylene glycol derivative is 1:0.8-1.2; more preferably, it is 1:1;

[0026] Preferably, the molar ratio of the polyethylene glycol derivative to the polyamino polymer is 1:1 to 3; more preferably, it is 1:2;

[0027] Preferably, the polyamino polymer is polylysine;

[0028] Preferably, the polylysine is purchased from Shanghai MacLean Biochemical Co., Ltd.;

[0029] Preferably, the mass concentration of the photocrosslinker in solution B is 0.2%;

[0030] Preferably, the photocrosslinking agent is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, CAS number: 106797-53-9;

[0031] Preferably, the 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone is purchased from Yuanye Biotechnology;

[0032] The present invention discovered that hydrogels obtained by soaking tannin with a PEGDA photocrosslinking system and hydrogels obtained by soaking tannin with a benzaldehyde-polyethylene glycol derivative-polyamino polymer crosslinking system both exhibited low adhesion of only approximately 1,000 to 2,000 Pa, failing to meet practical application requirements. However, the present invention creatively discovered that hydrogels obtained by combining the PEGDA photocrosslinking system with the benzaldehyde-polyethylene glycol derivative-polyamino polymer crosslinking system and soaking tannin exhibited significantly enhanced adhesion, with adhesion strength exceeding even the combined adhesion strengths of the two systems alone, reaching levels exceeding 7,000 Pa and, under certain preferred conditions, exceeding 20,000 Pa. This demonstrates that the PEGDA photocrosslinking and the benzaldehyde-polyethylene glycol derivative-polyamino polymer crosslinking in the present invention system create a synergistic effect: a 1+1>2 effect.

[0033] The inventors also discovered that if a larger amount of polyamino polymer is added, the benzaldehyde-polyethylene glycol derivative and the polyamino polymer tend to gel prematurely, affecting the photocrosslinking of PEGDA. This causes uncrosslinked PEGDA to be lost from the gel when soaked in tannin, and the PEGDA cannot fully synergize with the benzaldehyde-polyethylene glycol derivative-polyamino polymer crosslinking system, resulting in limited improvement in adhesion performance.

[0034] Preferably, the pH of the solution B is greater than 8;

[0035] Further preferably, the pH of the solution B is ≥8.8;

[0036] More preferably, the pH of the solution B is >11;

[0037] More preferably, the pH of the solution B is 11.3;

[0038] The inventors discovered that while a mixed crosslinking system of PEGDA photocrosslinking and benzaldehyde-polyethylene glycol derivative-polyamino polymer crosslinking in a slightly acidic environment can solidify into a gel, the benzaldehyde-polyethylene glycol derivative and polyamino polymer do not react and are lost from the gel when soaked in tannin, failing to synergize with PEGDA to enhance adhesion. Therefore, the present invention specifically adjusts the amount of polylysine and the pH of the mixed crosslinking system to balance the crosslinking speed and degree of the two crosslinking systems, resulting in a uniform combination of the two gels and significantly improving the adhesion properties of the hydrogel. Furthermore, the crosslinking system of the present invention is highly compatible with iodine-containing polyethylene glycol derivatives. When iodine-containing polyethylene glycol derivatives are used for crosslinking to impart developer functionality to the hydrogel, the resulting hydrogel still exhibits an adhesion strength exceeding 20,000 Pa.

[0039] Preferably, the time for the cross-linking reaction by ultraviolet irradiation is 0.5 to 2 hours; more preferably, it is 1 hour;

[0040] Preferably, the mass concentration of the tannin solution is 8-15%; more preferably, it is 10%;

[0041] Preferably, the soaking time in step S4 is 20 to 40 hours; more preferably, it is 24 hours;

[0042] Preferably, the step S4 further comprises drying the adhesive hydrogel to obtain an adhesive hydrogel dry glue;

[0043] Preferably, the drying condition is room temperature, vacuum drying for 20 to 40 hours;

[0044] Another aspect of the present invention provides an adhesive hydrogel prepared by the method for preparing the adhesive hydrogel.

[0045] Another aspect of the present invention provides an application of the adhesive hydrogel prepared by the above-mentioned method for preparing the adhesive hydrogel, which is used for adhesion or development.

[0046] Preferably, the adhesion includes adhesion on biological tissues, polymer materials, and metal materials.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] 1. The mixed crosslinking system of PEGDA photocrosslinking and benzaldehyde-based polyethylene glycol derivative-polyamino polymer crosslinking of the present invention can play a synergistic role after soaking in tannin, greatly improving the adhesion performance of the hydrogel;

[0049] 2. The adhesive hydrogel of the present invention can achieve good adhesion effects on the surfaces of various materials such as biological tissues, polymer materials, and metal materials;

[0050] 3. The present invention balances the crosslinking speed and degree of the mixed system by specifically adjusting the amount of polylysine and the pH of the mixed crosslinking system, thereby significantly improving the adhesion strength of the hydrogel;

[0051] 4. The present invention uses covalent bonds to stably fix the iodine-containing groups in the main chain of the hydrogel, so that the adhesive hydrogel also has a development function, achieving long-term development while ensuring the development effect, and can be used to guide radiotherapy positions, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 This is the H NMR spectrum of the iodobenzaldehyde-terminated star-shaped 8-arm polyethylene glycol prepared in Example 2;

[0053] Figure 2 Graph showing the adhesion strength results of the hydrogels of Examples 1-2 and Comparative Examples 1-4;

[0054] Figure 3 This is a diagram showing the development test results of the hydrogel dry glue of Example 2;

[0055] Figure 4 Figures showing the adhesion of the hydrogel prepared in Example 1 to different materials: a) adhesion to silicone gloves; b) adhesion to plastic; c) adhesion to sausage casing; d) adhesion to PTFE block; e) adhesion to metal; and f) adhesion to both metal and sausage casing. DETAILED DESCRIPTION

[0056] The concentrations of the solutions in the examples are all by mass, and all reagents were purchased from the preferred sources in the summary of the invention.

[0057] Example 1

[0058] This embodiment provides an adhesive hydrogel, and a preparation method thereof comprises the following steps:

[0059] S1: Prepare a 20% PEGDA (700) solution with water, prepare a 20% polyethylene glycol derivative solution with 0.02 M phosphate buffer, and mix equal volumes of the PEGDA solution and the polyethylene glycol derivative solution to obtain solution A;

[0060] S2: A polylysine solution with a concentration of 0.31725% was prepared, and a photocrosslinker, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (CAS No. 106797-53-9, purchased from Yuanye Biotechnology), was added to bring the concentration of the photocrosslinker to 0.2%. The pH was adjusted to 11.30 with a 10 M aqueous sodium hydroxide solution to obtain solution B.

[0061] S3: Mix equal volumes of solution A and solution B and irradiate with UV for 1 h for cross-linking reaction to obtain a gel;

[0062] S4: Soaking the gel obtained in step S3 in a 10% tannin solution for 24 hours to obtain an adhesive hydrogel; and vacuum drying the adhesive hydrogel at 25° C. for 24 hours to obtain a dry hydrogel.

[0063] The polyethylene glycol derivative is a star-shaped 8-arm polyethylene glycol terminated with benzaldehyde groups.

[0064] Example 2

[0065] This embodiment provides an adhesive hydrogel, the preparation method of which is the same as that of Example 1, except that the polyethylene glycol derivative is a star-shaped 8-arm polyethylene glycol terminated with iodinated benzaldehyde groups;

[0066] The iodobenzaldehyde-terminated star-shaped 8-arm polyethylene glycol is prepared by the following method:

[0067]

[0068] PEG(OH)8 (7g), triiodobenzoic acid (1.6g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.48g), and DMAP (0.37g) were added to a 50mL eggplant bottle, dissolved with 15mL dichloromethane, and stirred at 25°C for 48h. After the reaction was completed, p-formylbenzoic acid (0.48g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.48g), and DMAP (0.37g) were added to the eggplant bottle, and stirred at 25°C for 48h. After the reaction was completed, the liquid was extracted with saturated brine / CH2Cl2 and concentrated. After precipitation with icy ether three times, it was vacuum dried to obtain a total of 4.5g of the product with a yield of 64.3%. The structure is as follows Figure 1 1 The H·NMR spectrum showed that triiodobenzoic acid and p-formylbenzoic acid were both linked to PEG through ester bonds.

[0069] Comparative Example 1

[0070] This comparative example provides an adhesive hydrogel, and its preparation method comprises the following steps:

[0071] S1: Prepare a 20% polyethylene glycol derivative solution in 0.02 M phosphate buffer as solution A;

[0072] S2: Prepare a 5% polylysine solution and adjust the pH to 8.8 with a 10 M sodium hydroxide solution to obtain solution B;

[0073] S3: Mix equal volumes of solution A and solution B to obtain a gel;

[0074] S4: Soaking the gel obtained in step S3 in a 10% tannin solution for 24 hours to obtain an adhesive hydrogel; and vacuum drying the adhesive hydrogel at room temperature to obtain a dry hydrogel.

[0075] The polyethylene glycol derivative is a star-shaped 8-arm polyethylene glycol terminated with benzaldehyde groups.

[0076] Comparative Example 2

[0077] This comparative example provides an adhesive hydrogel, and its preparation method comprises the following steps:

[0078] A 20% PEGDA (700) solution was prepared with water, and a photocrosslinker, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (CAS No. 106797-53-9, purchased from Yuanye Biotechnology), was added to adjust the concentration of the photocrosslinker in the solution to 0.1%. The pH was adjusted to 8.8 with a 10 M sodium hydroxide aqueous solution, and the solution was irradiated with ultraviolet light for 1 h for a crosslinking reaction to obtain a gel.

[0079] The gel is immersed in a 10% tannin solution for 24 hours to obtain an adhesive hydrogel; and the adhesive hydrogel is vacuum-dried at room temperature to obtain a dry hydrogel.

[0080] Comparative Example 3

[0081] This comparative example provides an adhesive hydrogel, and its preparation method comprises the following steps:

[0082] S1: Prepare a 20% PEGDA (700) solution with water, prepare a 20% polyethylene glycol derivative solution with 0.02 M phosphate buffer, and mix equal volumes of the PEGDA solution and the polyethylene glycol derivative solution to obtain solution A;

[0083] S2: A 5% polylysine solution was prepared, and a photocrosslinker, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (CAS No. 106797-53-9, purchased from Yuanye Biotechnology, was added to bring the concentration of the photocrosslinker to 0.2%. The pH was adjusted to 8.8 with a 10 M aqueous sodium hydroxide solution to obtain solution B.

[0084] S3: Mix equal volumes of solution A and solution B and irradiate with UV for 1 h for cross-linking reaction to obtain a gel;

[0085] S4: Soaking the gel obtained in step S3 in a 10% tannin solution for 24 hours to obtain an adhesive hydrogel; and vacuum drying the adhesive hydrogel at room temperature to obtain a dry hydrogel.

[0086] The polyethylene glycol derivative is a star-shaped 8-arm polyethylene glycol terminated with benzaldehyde groups.

[0087] Comparative Example 4

[0088] This comparative example provides an adhesive hydrogel, and its preparation method comprises the following steps:

[0089] S1: Prepare a 20% PEGDA (700) solution with water, prepare a 20% polyethylene glycol derivative solution with 0.02 M phosphate buffer, and mix equal volumes of the PEGDA solution and the polyethylene glycol derivative solution to obtain solution A;

[0090] S2: Prepare a 5% polylysine solution, add a photocrosslinker 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (CAS No. 106797-53-9, purchased from Yuanye Biotechnology) to a concentration of 0.2%, and do not adjust the pH to obtain solution B.

[0091] S3: Mix equal volumes of solution A and solution B and irradiate with UV for 1 h for cross-linking reaction to obtain a gel;

[0092] S4: Soaking the gel obtained in step S3 in a 10% tannin solution for 24 hours to obtain an adhesive hydrogel; and vacuum drying the adhesive hydrogel at room temperature to obtain a dry hydrogel.

[0093] The polyethylene glycol derivative is a star-shaped 8-arm polyethylene glycol terminated with benzaldehyde groups.

[0094] Performance Testing

[0095] 1. Adhesion strength test

[0096] 0.2g of the hydrogel dry glue prepared in Examples 1-2 and Comparative Examples 1-4 was soaked in deionized water for 1 minute. The wet dry glue was then placed between two wet sausage casings and pressed with a 200g weight for 10 minutes. The two sausage casings were placed on the two clamps of a universal tensile testing machine and separated along the direction of the sausage casings. The maximum separation force was measured. The final adhesion strength was then obtained by measuring the adhesion area, as shown in Figure 2. Figure 2 shown.

[0097] 2. Development strength test

[0098] The hydrogel prepared in Example 2 and the rat were placed under CT and photographed. The developed photos are as follows: Figure 3 As shown, it can be seen that under CT, its development intensity is close to that of rat bone, which is 218.

[0099] 3. Verification of adhesion with other materials

[0100] The hydrogel prepared in Example 1 was placed directly above the materials to be adhered, and a positive pressure of 20 N was applied and maintained for 30 seconds. The adhesion between the hydrogel and the materials was observed. The materials to be adhered included silicone gloves, plastic, sausage casing, PTFE block, metal, and both metal and sausage casing. The adhesion was as follows: Figure 4 shown.

Claims

1. A method for preparing an adhesive hydrogel, characterized in that: The following steps are involved: S1: preparing a PEGDA solution and a polyethylene glycol derivative solution respectively, and mixing the PEGDA solution and the polyethylene glycol derivative solution to obtain solution A; S2: Prepare a polyamino polymer solution, add a photocrosslinker, and adjust the pH to obtain solution B; S3: Mixing solution A and solution B, irradiating with ultraviolet light for cross-linking reaction, and obtaining a gel; S4: soaking the gel obtained in step S3 in a tannin solution to obtain an adhesive hydrogel; The polyethylene glycol derivative is a star-shaped multi-arm polyethylene glycol terminated with a benzaldehyde group or a star-shaped multi-arm polyethylene glycol terminated with an iodinated benzaldehyde group; The polyamino polymer is polylysine; The photocrosslinking agent is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone; The mass ratio of the PEGDA to the polyethylene glycol derivative is 1:0.8-1.2; The molar ratio of the polyethylene glycol derivative to the polyamino polymer is 1:1 to 3; The pH of the solution B is greater than 8.

2. The method for preparing the adhesive hydrogel according to claim 1, wherein: The solvent of the polyethylene glycol derivative solution is 0.02M phosphate buffer.

3. The method for preparing the adhesive hydrogel according to claim 1, wherein: The step S4 further includes drying the adhesive hydrogel to obtain an adhesive hydrogel dry glue.

4. An adhesive hydrogel prepared according to the method for preparing an adhesive hydrogel according to any one of claims 1 to 3.

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