Biological adhesive with stable performance as well as preparation method and application of biological adhesive

Abstract

The invention belongs to the technical field of biomedical materials, and particularly relates to a biological adhesive with stable performance and a preparation method and application thereof. Specifically, by regulating and controlling the mixing mode of the active ester and the amino cross-linking agent, an acidic polylysine hydrochloride aqueous solution is adopted as the amino cross-linking agent, the active ester is directly dissolved in the polylysine hydrochloride aqueous solution, and the formed solution mixing system is stable in performance, can be stably stored for 6 hours at room temperature, can be prepared by an operator before an operation, and is free of secondary pollution. And the device can be immediately used at any time in the operation, has good batch stability, and avoids individual difference, so that the device has important application value and market prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical materials, and in particular relates to a bioadhesive with stable performance, a preparation method and an application thereof. Background Art

[0002] The information disclosed in the background of the invention is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Bioadhesives can be used for closed hemostasis, skin tissue regeneration, wound closure, and postoperative repair. Stable performance is essential for effectiveness. Currently available products consist of an active ester dissolved in an acidic buffer (Component A) and an amino crosslinker dissolved in an alkaline buffer (Component B), which are blended using a double syringe. Mixing is performed via a nozzle, resulting in a short mixing time, curing within seconds, and rapid gel formation. This hinders thorough mixing of the active ester and amino crosslinker, leading to large variations in mechanical strength, inconsistent degradation times, and individual variability. Using polyethyleneimine (PEI) as a crosslinker can lead to inadequate mixing, incomplete neutralization of the PEI, and the resulting free PEI, which can easily cause tissue inflammatory reactions. Furthermore, when the active ester is dissolved in an acidic solution, it readily hydrolyzes to form the corresponding carboxyl groups and N-hydroxysuccinimide (NHS), which interfere with its coupling reaction with other biomolecules (such as proteins and peptides), compromising its effectiveness in bioconjugation applications. These steps require medical personnel to strictly control operating time during use.

[0004] Prior art reports describe a surgical sealant kit and its use in brain and spinal surgery. The kit comprises an acidic buffer solution containing a crosslinker and a polyethylene glycol derivative, which is then mixed to produce an acidic mixed solution. This acidic mixed solution is then mixed with an alkaline buffer solution and applied to the wound surface. This improved dissolution speeds up the crosslinking reaction and the sealant's gelation rate, resulting in a gelation time of less than 1 second. However, the inventors have discovered that excessively fast gelation rates can lead to uneven mixing and syringe nozzle clogging, particularly when using small amounts, and place high demands on the operator. Summary of the Invention

[0005] To address the shortcomings of the aforementioned prior art, the present invention provides a stable bioadhesive, its preparation method, and its application. Specifically, the present invention regulates the mixing method of an active ester and an amino crosslinker, employing an acidic aqueous solution of polylysine hydrochloride as the amino crosslinker. The active ester is directly dissolved in the aqueous solution of polylysine hydrochloride. The resulting solution mixture exhibits stable performance and can be stored stably at room temperature for 6 hours. The operator can prepare the solution before surgery and use it immediately at any time during the procedure. The solution also exhibits excellent batch stability, minimizing individual variability. Based on the aforementioned research findings, the present invention was completed.

[0006] In order to achieve the above technical objectives, the present invention relates to the following technical solutions: The first aspect of the present invention provides a bioadhesive with stable performance, wherein the raw materials of the bioadhesive include component A, component B and its solvent, and a pH adjuster; wherein the component A is multi-arm polyethylene glycol succinimidyl glutarate (n-arm-PEG-SG); The component B is polylysine hydrochloride, and the solvent of the component B is water; The pH adjuster can be a sodium bicarbonate / sodium carbonate aqueous solution; the molar ratio of sodium bicarbonate to sodium carbonate in the sodium bicarbonate / sodium carbonate aqueous solution is (0.1-10):1, and the pH value of the pH adjuster is 9-11.

[0007] In another embodiment of the present invention, the molecular weight of the n-arm-PEG-SG is 10-30K, and n can be selected from 4 to 8, such as 4, 6 or 8; The degree of polymerization of the polylysine hydrochloride is 10 to 50; The molar ratio of the active group of the multi-arm polyethylene glycol succinimidyl glutarate (i.e., the succinimidyl ester group at the end of the multi-arm polyethylene glycol succinimidyl glutarate (n-arm-PEG-SG)) and the amino group of polylysine hydrochloride is (1-10):1. By controlling the appropriate ratio range, low gel strength, high swelling rate, incomplete curing, and unstable performance caused by insufficient or excessive cross-linking can be effectively avoided, while effectively maintaining the stability of the premix and regulating the gel properties.

[0008] In the present invention, the water is sterile water for injection, thereby ensuring the safety of use.

[0009] A second aspect of the present invention provides a method for preparing the above-mentioned bioadhesive, the method comprising: Component B is dissolved in a solvent of component B to obtain a solution containing component B, and then component A is dissolved in the solution containing component B to obtain a mixed solution.

[0010] Furthermore, the mixed solution is evenly mixed with a pH regulator and then sprayed to obtain the bioadhesive.

[0011] In the present invention, the step of mixing the mixed solution and the pH regulator and then spraying can be achieved by any existing double syringe; Furthermore, after the mixed solution is prepared, it can be stored at room temperature for no more than 6 hours; and then mixed with a pH regulator.

[0012] A third aspect of the present invention provides a surgical sealant kit, comprising at least the above-mentioned stable bioadhesive. Furthermore, the surgical sealant kit may also comprise other commonly used materials for kits, such as a double syringe, instructions, etc., which are not specifically limited herein.

[0013] A fourth aspect of the present invention provides use of the above-mentioned bioadhesive and surgical sealant kit in the preparation of medical devices.

[0014] The medical device has excellent performance stability and can be used for closed hemostasis, skin tissue regeneration, wound closure and postoperative repair, etc., without specific limitation here.

[0015] In the present invention, the medical device may be a drug-device combination medical device, thereby further expanding the scope of use of the above-mentioned bioadhesive or surgical sealing kit.

[0016] Beneficial technical effects of one or more of the above technical solutions: (1) The above technical solution first dissolves the active ester (PEG-SG) in a polylysine hydrochloride aqueous solution. After being fully mixed, the mixed system is blended with a pH regulator through a double syringe before use. It has been verified that individual differences can be avoided. There is no difference in the mechanical strength of the gel each time it is used, and the degradation time is consistent; (2) After the powdered active ester of the current market products is mixed with the acidic buffer solution, in order to ensure the best performance of the product, it is required to be used within 1 hour at room temperature. The operator can only prepare it for use after the suture is completed and cannot prepare it in advance; it cannot be used in time for emergencies during surgery; while the above technical solution adjusts the mixing method of the active ester and the amino cross-linking agent, uses the acidic polylysine hydrochloride aqueous solution as the amino cross-linking agent, and directly dissolves the active ester in the polylysine hydrochloride aqueous solution. The resulting solution mixture system has stable performance and can be stably stored at room temperature for 6 hours. The operator can prepare it before surgery and use it immediately at any time during surgery, solving the problem that similar products cannot be used in time for emergencies.

[0017] (3) The adhesive prepared by the method provided by the above technical solution has a gelling time of 3 to 10 seconds, which can reduce the risk of syringe blockage during the spraying process and provide the operator with sufficient use time.

[0018] (4) The adhesive prepared by the method provided by the above technical solution has a stable cross-linking degree. Since the swelling rate of the adhesive depends on the cross-linking degree, a stable swelling rate can reflect the stability of the cross-linking degree. By repeatedly testing the swelling rates of the adhesives prepared by the present invention and the prior art, it can be proved that the cross-linking degree of the adhesive provided by the present invention is stable.

[0019] (5) Currently, all products on the market contain PEI, which is the main component of the amino cross-linking agent. PEI is prone to cause tissue inflammatory reactions. Through experimental comparison and exploration, the above technical solution has been found to use polylysine as the amino cross-linking agent for preparing adhesives. Its degradation product is lysine, which provides essential amino acids for the body. Therefore, it has important application value and market prospects. DETAILED DESCRIPTION

[0020] It should be noted that the following detailed descriptions are exemplary and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0021] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments of the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0022] As mentioned above, in the prior art, active esters need to be used immediately (within 1 h at room temperature) after being dissolved in an acidic buffer. This is because the succinimide ester group will be destroyed under acidic conditions and gradually hydrolyzed to form the corresponding carboxyl group and N-hydroxysuccinimide (NHS), which in turn affects its coupling reaction with other biomolecules (such as proteins, peptides, etc.), thereby affecting its effectiveness in bioconjugation applications.

[0023] Through research, the inventors unexpectedly discovered that mixing active esters with polylysine hydrochloride results in relatively stable performance, allowing for stable storage at room temperature for over 6 hours. Specifically, the active ester group has high reactivity and can react with the amino groups in polylysine to form amide bonds, thereby attaching polyethylene glycol chains to the polylysine molecules. The inventors discovered that different polylysine raw material forms (polylysine, polylysine hydrochloride, different pH values, different raw material selection, and consequently different buffers) affect the performance of the adhesive. By comparing and exploring different mixing methods of active esters and amino crosslinkers, and testing stability and gelation performance, such as gelation rate, burst strength, and swelling ratio, the inventors were able to achieve an adhesive that exhibits excellent gelation and stable performance even after storage at room temperature for 6 hours after mixing the active ester and amino crosslinker and then adjusting the pH to form an adhesive.

[0024] In view of this, a typical embodiment of the present invention provides a bioadhesive with stable performance, wherein the raw materials of the bioadhesive include component A, component B and its solvent, and a pH adjuster; wherein the component A is multi-arm polyethylene glycol succinimidyl glutarate (n-arm-PEG-SG); The component B is polylysine hydrochloride, and the solvent of the component B is water; The pH adjuster can be a sodium bicarbonate / sodium carbonate aqueous solution; the molar ratio of sodium bicarbonate to sodium carbonate in the sodium bicarbonate / sodium carbonate aqueous solution is (0.1-10):1, and the pH value of the pH adjuster is 9-11.

[0025] In another embodiment of the present invention, the molecular weight of the n-arm-PEG-SG is 10-30K, and n can be selected from 4 to 8, such as 4, 6 or 8; The degree of polymerization of the polylysine hydrochloride is 10 to 50; The molar ratio of the active group of the multi-arm polyethylene glycol succinimidyl glutarate (i.e., the succinimidyl ester group at the end of the multi-arm polyethylene glycol succinimidyl glutarate (n-arm-PEG-SG)) and the amino group of polylysine hydrochloride is (1-10):1. By controlling the appropriate ratio range, low gel strength, high swelling rate, incomplete curing, and unstable performance caused by insufficient or excessive cross-linking can be effectively avoided, while effectively maintaining the stability of the premix and regulating the gel properties.

[0026] In the present invention, the water is sterile water for injection, thereby ensuring the safety of use.

[0027] In another embodiment of the present invention, a method for preparing the above-mentioned bioadhesive is provided, the method comprising: Component B is dissolved in a solvent of component B to obtain a solution containing component B, and then component A is dissolved in the solution containing component B to obtain a mixed solution.

[0028] Furthermore, the mixed solution is evenly mixed with a pH regulator and then sprayed to obtain the bioadhesive.

[0029] In the present invention, the step of mixing the mixed solution and the pH regulator and then spraying can be achieved by any existing double syringe; Furthermore, after the mixed solution is prepared, it can be stored at room temperature for no more than 6 hours; and then mixed with a pH regulator.

[0030] In another specific embodiment of the present invention, a surgical sealant kit is provided, which contains at least the above-mentioned stable bioadhesive. Furthermore, the surgical sealant kit may also contain other commonly used materials for kits, such as a double syringe, instructions, etc., which are not specifically limited here.

[0031] In another embodiment of the present invention, there is provided use of the above-mentioned bioadhesive and surgical sealant kit in the preparation of medical devices.

[0032] The medical device has excellent performance stability and can be used for closed hemostasis, skin tissue regeneration, wound closure and postoperative repair, etc., without specific limitation here.

[0033] The present invention is further explained by the following examples, but is not intended to limit the present invention. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention.

[0034] Table 1 Component settings of each embodiment

[0035] Note: A solution* is component A dissolved in active ester solvent (solvent for component A), B solution # Component B is dissolved in pH adjuster (solvent for component B) Experimental Group 1 Prepare 4 mL of adhesive: dissolve 0.4 g of 4-arm-PEG-SG 10K in 2 mL of sterile water for injection, then dissolve 0.2 g of 4-arm polyethylene glycol amino (4-arm-PEG-NH210K) in 2 mL of sterile water for injection. Immediately mix the two components through a syringe nozzle to obtain adhesive sample 1.

[0036] Experimental Group 2 Prepare 4 mL of adhesive: dissolve 0.8 g of 4-arm-PEG-SG 20K in 2 mL of sterile water for injection, then dissolve 0.2 g of 4-arm-PEG-NH2 (10K) in 2 mL of sterile water for injection. Immediately mix the two components through a syringe nozzle to obtain adhesive sample 2.

[0037] Experimental Group 3 Prepare 4 mL of adhesive: dissolve 0.2 g of 8-arm-PEG-SG 10K in 2 mL of sterile water for injection, then dissolve 0.2 g of 4-arm-PEG-NH2 (10K) in 2 mL of sterile water for injection. Immediately mix the two components through a syringe nozzle to obtain an adhesive sample.

[0038] Experimental Group 4 Prepare 4 mL of adhesive: dissolve 0.4 g of 8-arm-PEG-SG 20K in 2 mL of sterile water for injection, then dissolve 0.2 g of 4-arm-PEG-NH2 (10K) in 2 mL of sterile water for injection. Immediately mix the two components through a syringe nozzle to obtain adhesive sample 4.

[0039] Experimental Group 5 Prepare 4 mL of adhesive: dissolve 0.4 g of 4-arm-PEG-SG 20K in 2 mL of sterile water for injection, and then dissolve 0.0051 g of 3200 Da basic polylysine in 2 mL of sterile water for injection, pH 9.2; immediately mix the above two components through a syringe nozzle to obtain adhesive sample 5.

[0040] Experimental Group 6 To prepare 4 mL of adhesive, dissolve 0.0051 g of 3200 Da poly-lysine hydrochloride in 2 mL of 0.05 M sodium tetraborate buffer (pH 9.2). Dissolve 0.4 g of 4-arm-PEG-SG 20K in 2 mL of sterile water for injection. Immediately mix the two components through a syringe to obtain Adhesive Sample 6.

[0041] Experimental Group 7 Prepare 4 mL of adhesive: dissolve 0.4 g of 4-arm-PEG-SG 20K in 2 mL of sterile water for injection, then dissolve 0.0034 mL of 50% 25K polyethyleneimine in 2 mL of sterile water for injection. Immediately mix the two components through a syringe nozzle to obtain adhesive sample 7.

[0042] Experimental Group 8 Prepare 4 mL of adhesive: dissolve 0.0051 g of 3200 Da polylysine hydrochloride in 2 mL of sterile water for injection to obtain a polylysine hydrochloride aqueous solution. Then, dissolve 0.4 g of 4-arm-PEG-SG (20K) in 2 mL of the aforementioned polylysine hydrochloride aqueous solution to form a mixed system. The mixed system is then immediately mixed with 2 mL of 0.05 M sodium tetraborate buffer (pH 9.2) via a syringe nozzle to obtain Adhesive Sample 8.

[0043] Experimental Group 9 Prepare 4 mL of adhesive: dissolve 0.0051 g of 3200 Da polylysine hydrochloride in 2 mL of sterile water for injection to obtain a polylysine hydrochloride aqueous solution. Then, dissolve 0.4 g of 4-arm-PEG-SG (20K) in the aforementioned 2 mL of the polylysine hydrochloride aqueous solution to form a mixed system. This mixture is then immediately mixed with 2 mL of 0.05 M sodium bicarbonate buffer (pH 9.2) through a syringe nozzle to obtain Adhesive Sample 9.

[0044] Example 1 Preparation of 4 mL of adhesive: Dissolve 0.0051 g of 3200 Da polylysine hydrochloride in 2 mL of sterile water for injection to obtain a polylysine hydrochloride aqueous solution; then dissolve 0.4 g of 4-arm-PEG-SG (20K) in the aforementioned 2 mL of polylysine hydrochloride aqueous solution to form a mixed system; prepare a sodium bicarbonate / sodium carbonate pH adjuster (pH 9.2) by thoroughly mixing 1.8 mL of 0.05 M sodium bicarbonate solution and 0.2 mL of 1 M sodium carbonate solution to obtain 2 mL of sodium bicarbonate / sodium carbonate pH adjuster; after 4-arm-PEG-SG (20K) was dissolved in the polylysine hydrochloride aqueous solution, the mixed system and the pH adjuster were mixed through a syringe nozzle immediately, 2 h, 6 h, and 12 h to obtain adhesive samples 10, 11, 12, and 13, respectively.

[0045] Comparative Example 1 To prepare 4 mL of adhesive, dissolve 0.4 g of 4-arm-PEG-SG 20K in 2 mL of acidic phosphate buffer as solution A, and dissolve 0.0051 g of 3200 Da poly-lysine hydrochloride in 2 mL of 0.05 M sodium tetraborate buffer (pH 9.2) as solution B. Immediately after preparation, and 2 h, 6 h, and 12 h later, solution A was mixed with solution B through a syringe nozzle to obtain adhesive samples 14, 15, 16, and 17, respectively.

[0046] Effect verification 1. Gel curing time Place a 3 mL round-bottom centrifuge tube equipped with a 6 × 3 mm micro magnetic stirring bar in the center of a magnetic stirrer. Rotate the stirring bar at a constant speed of 1000 rpm. Take 0.2 mL of the uncured gel product and inject it into the bottom of the round-bottom centrifuge tube. Use a calibrated stopwatch to record the gel curing time, starting from the injection of the gel until the stirring bar stops rotating. Record the time it takes to gel.

[0047] 2. Swelling rate Take about 1 g of the prepared hydrogel sample, shape it into a cylinder with a diameter of about 15.3 mm and a height of about 5.5 mm (prepared and taken out in a 10 mL syringe), and place it in a 50 mL beaker. Add physiological saline buffer preheated to 37 ± 1°C, and the mass of the buffer is 40 times the test amount. Seal the beaker and place it in a 37 ± 1°C incubator. After 24 hours, take out the sample, absorb the surface moisture with filter paper, and weigh it accurately. Calculate the gel swelling rate according to the following formula.

[0048]

[0049] 3. Bursting strength Take a highly elastic hog casing and secure it to the funnel structure of the test device. Completely wrap it with a rubber clip and secure it tightly, ensuring that liquid does not leak through the binding. Use a punch with a 3mm outer diameter needle to create a hole. Spray 0.5mL of the hydrogel product onto the hole (control the thickness to be 1.6mm ± 0.4mm) to completely seal the hole. After waiting for 5 minutes, apply pressure to the hydrogel from below the casing hole at a rate of 70mmHg / min until the hydrogel breaks. Record the pressure at this point.

[0050] 4. In vitro degradation time The prepared hydrogel was placed in a phosphate buffer solution with a pH of 7.4 and is isotonic with blood at 37±1°C and observed daily until it became invisible to the naked eye. This was recorded as the in vitro degradation time of the gel.

[0051] 5. Subcutaneous Implantation Experiment According to GB / T 16886.6-2022 "Biological Evaluation of Medical Devices Part 6: Local Reactions Test after Implantation", the sample size is 10 mm in diameter and 0.5 mm in thickness.

[0052] 6. Cytotoxicity Assay The test was conducted in accordance with GB / T 16886.5-2017, "Biological Evaluation of Medical Devices - Part 5: In Vitro Cytotoxicity Tests." Results were calculated as the ratio of the mean absorbance of the experimental group to the mean absorbance of the control group. A ratio less than 70% was considered cytotoxic.

[0053] Experiment 1: Selection of PEG-SG Selection Principle: 4-arm-PEG-NH2 (10K) was used to react with different PEG-SGs, with a molar ratio of active groups to amino groups of 2:1. Other preparation steps were identical. Experimental Groups 1 to 4 were set up. The gel curing time and burst strength of the sealing materials obtained in each example were measured. Based on the test results in Table 2, it was determined that 4-arm-PEG-SG 20K provided the active groups.

[0054] Table 2 Test results of each group

[0055] Experiment 2: Selection of amino cross-linking agents Selection Principle: 4-arm-PEG-SG 20K was selected to provide active groups for reaction with different crosslinkers. The molar ratio of active groups to amino groups was 2:1, and the other preparation steps were the same. Experimental Groups 2, 5, and 7 were set up. The gel curing time, burst strength, swelling ratio, and subcutaneous implantation reaction of the sealing material obtained in each example were measured. The results are shown in Table 3. Based on the test results, polylysine was determined to be the crosslinker.

[0056] Table 3 Test results of each group

[0057] Experiment 3: Polylysine selection Selection Principle: 4-arm-PEG-SG 20K was used to provide reactive groups, which reacted with different types of polylysine at a molar ratio of 2:1. Experimental Groups 5 and 6 were set up. The difference between the groups was the polylysine form used as the amino crosslinker: one was basic polylysine, and the other was polylysine hydrochloride. The gel curing time, burst strength, swelling ratio, and in vitro degradation of the sealing materials obtained in each example were measured. The results are shown in Table 4. According to the test results, the sealing material prepared in Experimental Group 6 performed better than that in Experimental Group 5, indicating the selection of polylysine hydrochloride as the amino crosslinker.

[0058] Table 4 Test results of each group

[0059] Experiment 4: Selection of hybrid method Selection principle: 4-arm-PEG-SG 20K was selected as the active group, polylysine hydrochloride was used as the crosslinker, and the molar ratio of active group to amino group was 2:1. Experimental groups 6 and 8 were set up; the difference between the two was the different mixing methods of the active ester and the crosslinker. The gel curing time, burst strength, swelling rate and in vitro degradation of the sealing material obtained in each example were measured. The results are shown in Table 4. The burst strength and swelling rate of sample 8 were better than those of sample 6, and the in vitro degradation met the requirements. Therefore, the mixing method of experimental group 8 was selected.

[0060] Experiment 5: Selection of alkaline buffer Selection principle: 4-arm-PEG-SG 20K is selected to provide active groups and polylysine hydrochloride is used as a cross-linking agent. The molar ratio of active groups to amino groups is 2:1. After dissolving 4-arm-PEG-SG 20K in a polylysine hydrochloride aqueous solution, it is mixed with different alkaline buffers in equal proportions. Experimental groups 8, 9 and Example 1 are set up, and the gel curing time, burst strength, swelling rate, in vitro degradation and cytotoxicity of the sealing materials obtained in each group are measured. The results are shown in Table 5. According to the test results, the mechanical properties of the adhesive prepared using only sodium bicarbonate buffer are inferior to those of the samples obtained using sodium tetraborate and sodium bicarbonate / sodium carbonate as buffers. However, from the perspective of cytotoxicity, sodium bicarbonate / sodium carbonate is preferred. Therefore, it is determined that the present invention uses 4-arm-PEG-SG20K to provide active groups, uses a cross-linking agent acidic polylysine hydrochloride aqueous solution as an active ester solvent, and uses a sodium bicarbonate / sodium carbonate buffer as a pH regulator to form an adhesive with stable performance.

[0061] Table 5 Test results of each group

[0062] Experiment 6: Performance Stability Test Components A and B in Example 1 and Comparative Example 1 are identical. In Example 1, 4-arm-PEG-SG was dissolved in a polylysine hydrochloride aqueous solution to create a mixed system. The mixture was then allowed to stand for 0, 2, 6, and 12 hours before being mixed with a pH adjuster via a spray nozzle to form a gel, yielding Samples 10 to 13. In Comparative Example 1, Solution A was prepared and allowed to stand for 0, 2, 6, and 12 hours before being mixed with Solution B via a spray nozzle to form a gel, yielding Samples 14 to 17. Each sample was tested 10 times to determine burst strength and in vitro degradation time. The test results are presented as mean ± standard deviation (Table 6). Performance stability was assessed, revealing greater individual variability in the Comparative Example group, with Solution A failing to form a gel after 2 hours of preparation.

[0063] Table 6 Test results of each group

[0064] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A bioadhesive with stable performance, characterized in that: The raw materials of the bioadhesive include component A, component B and its solvent and a pH regulator; wherein the component A is multi-arm polyethylene glycol succinimidyl glutarate (n-arm-PEG-SG); The component B is polylysine hydrochloride, and the solvent of the component B is water; The pH regulator is a sodium bicarbonate / sodium carbonate aqueous solution.

2. The bioadhesive according to claim 1, wherein The molar ratio of sodium bicarbonate to sodium carbonate in the sodium bicarbonate / sodium carbonate aqueous solution is (0.1-10):1, and the pH value of the pH adjuster is 9-11.

3. The bioadhesive according to claim 1, wherein The molecular weight of the n-arm-PEG-SG is 10-30K, and n is selected from 4-8, further including 4, 6 or 8.

4. The bioadhesive according to claim 1, wherein The degree of polymerization of the polylysine hydrochloride is 10-50.

5. The bioadhesive according to claim 1, wherein The molar ratio of the active groups of the multi-arm polyethylene glycol succinimidyl glutarate to the amino groups of polylysine hydrochloride is (1-10):

1.

6. The bioadhesive according to any one of claims 1 to 5, wherein The water is sterile water for injection.

7. The method for preparing the bioadhesive according to any one of claims 1 to 6, characterized in that: The preparation method comprises: Component B is dissolved in a solvent of component B to obtain a solution containing component B, and then component A is dissolved in the solution containing component B to obtain a mixed solution.

8. The preparation method according to claim 7, wherein The mixed solution is mixed with a pH regulator and then sprayed to obtain the bioadhesive; Furthermore, after the mixed solution is prepared, it can be stored at room temperature for no more than 6 hours; and then mixed with a pH regulator.

9. A surgical sealant kit, characterized in that: The surgical sealant kit comprises at least the stable bioadhesive according to any one of claims 1 to 6; further, the surgical sealant kit further comprises a double syringe and instructions.

10. Use of the bioadhesive according to any one of claims 1 to 6 or the surgical sealant kit according to claim 9 in the preparation of medical devices.

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