A stable performance biological adhesive and its preparation method and application

Abstract

The application 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 a mixing mode of active ester and amino cross-linking agent, using an acidic polylysine hydrochloride aqueous solution as the amino cross-linking agent, directly dissolving the active ester in the polylysine hydrochloride aqueous solution, the solution mixing system formed has stable performance, can be stored at room temperature for 6 hours, an operator can prepare before operation, and can be used at any time during operation, and has good batch stability, avoids individual differences, and therefore has important application value and market prospect.

Description

TECHNICAL FIELD

[0001] The present application 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. BACKGROUND

[0002] The information disclosed in the background of the present application is only intended to increase the understanding of the overall background of the present application, and should not necessarily be regarded as acknowledging or implicitly suggesting that this information constitutes prior art known to those of ordinary skill in the art.

[0003] The biological adhesive can be used for occlusive hemostasis, skin tissue regeneration, wound closure and postoperative repair, and its stable performance is a prerequisite for effectiveness. The currently marketed products are all active ester dissolved in acidic buffer solution as component A, amino crosslinking agent dissolved in alkaline buffer solution as component B, and used by mixing through a double syringe. The mixing process is mixed through a nozzle, the mixing time is short, and the adhesive is quickly formed in a few seconds, which is not conducive to the full mixing of active ester and amino crosslinking agent, the mechanical strength of the adhesive material formed is large, the degradation time is inconsistent, and there is individual difference in use; if polyethyleneimine (PEI) is used as a crosslinking agent, the mixing may not be sufficient, the PEI is not completely neutralized, and free PEI can easily cause inflammatory reaction of the tissue; and after the active ester is dissolved in an acidic solution, it is easy to hydrolyze to form corresponding carboxyl and N-hydroxysuccinimide (NHS), which affects its coupling reaction with other biomolecules (such as proteins, polypeptides, etc.), and the effect in biological coupling application is affected. The above steps require medical personnel to strictly control the operation time during use.

[0004] The prior art reports a surgical sealant kit and its application in brain and spinal surgery, which mixes the acid buffer solution containing the crosslinking agent with the polyethylene glycol derivative to obtain an acid mixed solution, and then mixes the acid mixed solution with the alkaline buffer solution and applies it on the wound. The improvement of the dissolution effect makes the crosslinking reaction proceed more quickly, and the sealant also gels faster, and the provided sealant gels in less than 1s. However, the inventors found that too fast gelation speed can easily cause uneven mixing and clogging of the syringe nozzle, especially in small dosage, and requires a higher operator. SUMMARY

[0005] Based on the deficiencies of the prior art, the present application provides a bioadhesive with stable performance, and a preparation method and application thereof. Specifically, the present application controls the mixing mode of active ester and amino crosslinking agent, uses an acidic polylysine hydrochloride aqueous solution as the amino crosslinking agent, directly dissolves the active ester in the polylysine hydrochloride aqueous solution, and forms a solution mixing system with stable performance, which can be stored at room temperature for 6 hours. The operator can prepare it before the operation, and it can be used at any time during the operation. The bioadhesive has good batch stability and avoids individual differences. Based on the above research results, the present application is completed.

[0006] To achieve the above technical purposes, the present application relates to the following technical solutions.

[0007] In a first aspect of the present application, a bioadhesive with stable performance is provided. The raw material composition of the bioadhesive includes component A, component B and its solvent, and a pH adjuster. The component A is n-arm-PEG-SG (multi-arm polyethylene glycol succinimidyl glutarate).

[0008] The component B is polylysine hydrochloride, and the solvent of the component B is water.

[0009] 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.

[0010] In another specific embodiment of the present application, the molecular weight of the n-arm-PEG-SG is 10-30K, and n can be selected from 4-8, such as 4, 6 or 8.

[0011] The degree of polymerization of the polylysine hydrochloride is 10-50.

[0012] 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)) to the amino group of the polylysine hydrochloride is (1-10):1. By controlling the appropriate ratio range, the performance instability caused by insufficient or excessive crosslinking, which leads to low gel strength, high swelling rate or incomplete solidification, can be effectively avoided, and the stability of the premixed solution can be effectively maintained, and the gel performance can be controlled.

[0013] In the present application, the water is all sterile water for injection, thereby ensuring the safety of use.

[0014] In a second aspect of the present application, a preparation method of the above bioadhesive is provided. The preparation method includes:

[0015] The B component is dissolved in a solvent of the B component to obtain a solution containing the B component, and then the A component is dissolved in the solution containing the B component to obtain a mixed solution.

[0016] Further, the mixed solution is mixed with a pH regulator and then sprayed to obtain the bioadhesive.

[0017] In the present application, the step of mixing the mixed solution with the pH regulator and then spraying can be realized by any existing double syringe.

[0018] Further, after the mixed solution is prepared, it can be stored at room temperature for no more than 6 hours, and then mixed with the pH regulator.

[0019] In a third aspect of the present application, a surgical sealant kit is provided, which at least comprises the above-mentioned performance-stable bioadhesive; further, the surgical sealant kit can also comprise other commonly used materials of the kit, such as a double syringe, an instruction manual, etc., which are not specifically limited herein.

[0020] In a fourth aspect of the present application, the above-mentioned bioadhesive and surgical sealant kit are provided for use in the preparation of a medical device.

[0021] The medical device has excellent performance stability and can be used for occlusive hemostasis, skin tissue regeneration, wound closure, postoperative repair, etc., which are not specifically limited herein.

[0022] In the present application, the medical device can be a medical device combined with a drug, thereby further expanding the use range of the above-mentioned bioadhesive or surgical sealant kit.

[0023] The above-mentioned one or more technical solutions have the following beneficial technical effects:

[0024] (1) In the above-mentioned technical solution, the active ester (PEG-SG) is first dissolved in a polylysine hydrochloride aqueous solution, and after being fully mixed, the mixed system is mixed with a pH regulator through a double syringe for use, which can avoid individual differences, has no difference in gel mechanical strength each time, and has consistent degradation time.

[0025] (2) The current market product powder active ester is mixed with an acidic buffer solution, 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 and use after the completion of the suture, and cannot be prepared in advance; in the operation, it cannot be used in time for unexpected situations; the technical scheme solves the problem that similar products cannot be used in time for unexpected situations, by regulating the mixing method of the active ester and the amino crosslinking agent, using an acidic polylysine hydrochloride aqueous solution as the amino crosslinking agent, and directly dissolving the active ester in the polylysine hydrochloride aqueous solution, the performance of the formed solution mixing system is stable, and the solution can be stably stored at room temperature for 6 hours, the operator can prepare before the operation, and the solution can be used immediately at any time during the operation.

[0026] (3) The adhesive prepared by the method provided in the above technical scheme has a gelation time of 3-10 seconds, which can reduce the risk of syringe blockage in the spraying process, and provides sufficient use time for the operator.

[0027] (4) The adhesive prepared by the method provided in the above technical scheme has stable crosslinking degree. The swelling rate of the adhesive depends on the crosslinking degree, and the stable swelling rate can reflect the stability of the crosslinking degree. By repeatedly testing the swelling rates of the adhesives prepared by the present application and the prior art, it can be proved that the adhesive provided by the present application has stable crosslinking degree.

[0028] (5) The current market products all contain PEI, which is the main component of the amino crosslinking agent, and PEI is easy to cause inflammatory reaction of the tissue. The amino crosslinking agent for preparing the adhesive in the above technical scheme is only polylysine, and the degradation product thereof is lysine, which provides essential amino acids for the body, and therefore has important application value and market prospect. DETAILED DESCRIPTION

[0029] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0030] It should be noted that the terms used herein are only for the purpose of describing specific embodiments, and are not intended to limit the exemplary embodiments according to the application. As used herein, the singular form is intended to include the plural form unless the context clearly indicates otherwise, and furthermore, it should be understood that when the terms "comprise" and / or "include" are used in the specification, there is a reference to the presence of a feature, step, operation, device, component and / or combinations thereof.

[0031] As described above, in the prior art, the active ester needs to be used immediately after being dissolved in an acidic buffer (within 1 h at room temperature), because the succinimidyl ester group will be destroyed under acidic conditions and gradually hydrolyzed to form the corresponding carboxyl and N-hydroxysuccinimide (NHS), thereby affecting the coupling reaction with other biomolecules (such as proteins, polypeptides, etc.), and affecting the effect in biological coupling applications.

[0032] The inventors have unexpectedly found that the active ester is relatively stable in performance when mixed with polylysine hydrochloride, and can be stored at room temperature for more than 6 h. Specifically, the active ester group has high reactivity and can react with the amino group in polylysine to form an amide bond, thereby connecting the polyethylene glycol chain to the polylysine molecule. The inventors have found that different forms of polylysine raw materials (polylysine, polylysine hydrochloride, different pH, different selection of raw materials, and different buffers) have an impact on the performance of the adhesive, and by comparing, exploring, and controlling different mixing methods of the active ester and the amino crosslinking agent, testing the stability and gelation effect, such as gelation speed, rupture strength, and swelling rate, the active ester and the amino crosslinking agent can be mixed and stored at room temperature for 6 h, and then the pH is adjusted to form an adhesive, which still has excellent gelation effect and stable performance.

[0033] Therefore, in one typical embodiment of the present application, a bioadhesive with stable performance is provided, which comprises A component, B component and its solvent, and pH adjusting agent; wherein the A component is n-arm-PEG-SG;

[0034] The B component is polylysine hydrochloride, and the solvent of the B component is water.

[0035] The pH adjusting agent can be 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 adjusting agent is 9-11.

[0036] In another embodiment of the present application, the molecular weight of the n-arm-PEG-SG is 10-30K, and n can be selected from 4-8, such as 4, 6 or 8.

[0037] The polydispersity of the polylysine hydrochloride is 10-50.

[0038] 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 the polylysine hydrochloride is (1-10):1; by controlling the appropriate ratio range, the low gel strength, high swelling rate or incomplete solidification caused by insufficient or excessive crosslinking is effectively avoided, the performance is stable, and the stability of the premixed solution is effectively maintained, and the gel performance is regulated.

[0039] In the present application, the water is all sterile injection water, thereby ensuring the safety in use.

[0040] In another specific embodiment of the present application, a preparation method of the above-mentioned biological adhesive is provided, and the preparation method comprises:

[0041] The B component is dissolved in a solvent of the B component to obtain a solution containing the B component, and then the A component is dissolved in the solution containing the B component to obtain a mixed solution.

[0042] Further, the mixed solution is mixed with a pH regulator and then sprayed, and the biological adhesive is obtained.

[0043] In the present application, the step of mixing the mixed solution with the pH regulator and then spraying can be realized by using any existing double syringe.

[0044] Further, after the mixed solution is prepared, it can be stored at room temperature for not more than 6 hours, and then mixed with the pH regulator.

[0045] In another specific embodiment of the present application, a surgical sealant kit is provided, and the surgical sealant kit at least comprises the above-mentioned biological adhesive with stable performance; further, the surgical sealant kit can further comprise other materials commonly used in kits, such as a double syringe, an instruction manual, etc., which are not specifically limited herein.

[0046] In another specific embodiment of the present application, the above-mentioned biological adhesive and the surgical sealant kit are used in the preparation of medical devices.

[0047] The medical devices have excellent performance stability, and can be used for closed hemostasis, skin tissue regeneration, wound closure, postoperative repair, etc., which are not specifically limited herein.

[0048] The present application is further explained and described by the following examples, but the examples do not constitute a limitation on the present application. It should be understood that the examples are only used to illustrate the present application and do not limit the scope of the present application.

[0049] Table 1: Component settings of each example

[0050]

[0051] Note: Solution A is A component dissolved in active ester solvent (A component solvent), Solution B is B component dissolved in pH adjuster (B component solvent) #

[0052] Experiment 1

[0053] Prepare 4 mL of adhesive: Dissolve 0.4 g of 4-arm-PEG-SG 10K in 2 mL of sterile water for injection, and dissolve 0.2 g of 4-arm-PEG-NH2 10K in 2 mL of sterile water for injection. Immediately mix the two components through an injection jet to obtain adhesive sample 1.

[0054] Experiment 2

[0055] Prepare 4 mL of adhesive: Dissolve 0.8 g of 4-arm-PEG-SG 20K in 2 mL of sterile water for injection, and dissolve 0.2 g of 4-arm-PEG-NH2 10K in 2 mL of sterile water for injection. Immediately mix the two components through an injection jet to obtain adhesive sample 2.

[0056] Experiment 3

[0057] Prepare 4 mL of adhesive: Dissolve 0.2 g of 8-arm-PEG-SG 10K in 2 mL of sterile water for injection, and dissolve 0.2 g of 4-arm-PEG-NH2 10K in 2 mL of sterile water for injection. Immediately mix the two components through an injection jet to obtain adhesive sample.

[0058] Experiment 4

[0059] Prepare 4 mL of adhesive: Dissolve 0.4 g of 8-arm-PEG-SG 20K in 2 mL of sterile water for injection, and dissolve 0.2 g of 4-arm-PEG-NH2 10K in 2 mL of sterile water for injection. Immediately mix the two components through an injection jet to obtain adhesive sample 4.

[0060] Experiment 5

[0061] Prepare 4 mL of adhesive: Dissolve 0.4 g of 4-arm-PEG-SG 20K in 2 mL of sterile water for injection, and dissolve 0.0051 g of 3200 Da basic polylysine in 2 mL of sterile water for injection, solution pH 9.2. Immediately mix the two components through an injection jet to obtain adhesive sample 5.

[0062] Experiment 6

[0063] ​Prepare 4 mL of adhesive: Dissolve 0.0051 g of 3200 Da polylysine hydrochloride in 2 mL of 0.05 M sodium tetraborate buffer (pH 9.2), and then 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 tip to obtain adhesive sample 6.

[0064] Experiment 7

[0065] 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 0.0034 mL of 50% mass concentration of 25K polyethyleneimine in 2 mL of sterile water for injection. Immediately mix the two components through a syringe tip to obtain adhesive sample 7.

[0066] Experiment 8

[0067] 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 polylysine hydrochloride aqueous solution as a mixed system; and then immediately mix the mixed system with 2 mL of 0.05 M sodium tetraborate buffer (pH 9.2) through a syringe tip to obtain adhesive sample 8.

[0068] Experiment 9

[0069] 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 polylysine hydrochloride aqueous solution as a mixed system; and then immediately mix the mixed system with 2 mL of 0.05 M sodium bicarbonate buffer (pH 9.2) through a syringe tip to obtain adhesive sample 9.

[0070] Example 1

[0071] Preparation of 4 mL adhesive: 0.0051 g 3200 Da polylysine hydrochloride was dissolved in 2 mL sterilized water for injection to obtain a polylysine hydrochloride aqueous solution; 0.4 g 4-arm-PEG-SG (20K) was then dissolved in the above 2 mL polylysine hydrochloride aqueous solution as a mixed system; a sodium bicarbonate / sodium carbonate pH adjuster (pH 9.2) was prepared, specifically 1.8 mL of 0.05 M sodium bicarbonate solution and 0.2 mL of 1 M sodium carbonate solution, which were mixed thoroughly to obtain 2 mL of the sodium bicarbonate / sodium carbonate pH adjuster; the mixed system was mixed with the pH adjuster through an injection nozzle immediately, 2 h, 6 h and 12 h after the 4-arm-PEG-SG (20K) was dissolved in the polylysine hydrochloride aqueous solution, to obtain adhesive samples 10, 11, 12 and 13, respectively.

[0072] Comparative Example 1

[0073] Preparation of 4 mL adhesive: 0.4 g 4-arm-PEG-SG 20K was dissolved in 2 mL acidic phosphate buffer to obtain solution A, and 0.0051 g 3200 Da polylysine hydrochloride was dissolved in 2 mL 0.05 M sodium tetraborate buffer (pH 9.2) to obtain solution B; solution A was mixed with solution B through an injection nozzle immediately, 2 h, 6 h and 12 h after solution A was prepared, to obtain adhesive samples 14, 15, 16 and 17, respectively.

[0074] Effect verification

[0075] 1. Gel solidification time

[0076] A 3 mL round-bottom centrifuge tube containing 6 x 3 mm or so micro magnetic stirring rods was placed in the center of a magnetic stirrer, and the stirring rods were rotated at a speed of 1000 rpm. 0.2 mL of the gel product before solidification was injected into the bottom of the round-bottom centrifuge tube, and a calibrated stopwatch was used to record the gel solidification time. The time was counted from the injection of the gel to the stop of the rotation of the stirring rod when the gel was solidified.

[0077] 2. Swelling rate

[0078] About 1 g of the prepared hydrogel sample was made into a cylinder with a diameter of about 15.3 mm and a height of about 5.5 mm (prepared in a 10 mL syringe and taken out), and then placed in a 50 mL beaker. Physiological saline buffer preheated to 37 ± 1 ℃ was added, and the mass of the buffer was 40 times that of the test sample. The beaker was sealed and placed in a 37 ± 1 ℃ incubator, and after 24 hours, the sample was taken out and the surface water was absorbed with filter paper. The sample was precisely weighed, and the gel swelling rate was calculated according to the following formula.

[0079]

[0080] 3. Breaking strength

[0081] Take the elastic pig casing and fix it on the funnel structure of the detection device, and wrap it completely with a rubber card and tighten it to ensure that the liquid does not leak at the bundling place. Use a puncher with a needle diameter of 3mm to punch a hole, take 0.5mL of hydrogel product and spray it on the hole (the thickness is controlled at 1.6mm±0.4mm), so that the punched hole is completely sealed. After waiting for 5min, apply pressure to the hydrogel from below the casing hole at a speed of 70mmHg / min until the hydrogel breaks, and record the pressure at this time.

[0082] 4. In vitro degradation time

[0083] Put the prepared hydrogel into a phosphate buffer with a pH of 7.4 at 37±1℃, and observe daily until it is not visible to the naked eye, and record the in vitro degradation time of the gel.

[0084] 5. Subcutaneous implantation experiment

[0085] According to GB / T 16886.6-2022 "Biological Evaluation of Medical Devices Part 6: Local Reaction Test after Implantation", the sample size is 10mm in diameter and 0.5mm in thickness.

[0086] 6. Cytotoxicity experiment

[0087] According to GB / T 16886.5-2017 "Biological Evaluation of Medical Devices Part 5: In Vitro Cytotoxicity Test", the results are calculated: the ratio of the average absorbance value of the experimental group to the average absorbance value of the control group, and the ratio is less than 70% is considered to have cytotoxicity.

[0088] Experiment 1: Selection of PEG-SG

[0089] Selection principle: 4-arm-PEG-NH2 (10K) is selected to react with different PEG-SG, the molar ratio of active groups and amino groups is 2:1, and other preparation steps are the same; Set up experimental groups 1~4; Measure the gel curing time and rupture strength of the sealing material obtained in each example, according to the test results in Table 2, determine that 4-arm-PEG-SG 20K provides active groups.

[0090] Table 2 Test results of each group

[0091]

[0092] Experiment 2: Selection of amino crosslinking agent

[0093] Selection principle: 4-arm-PEG-SG 20K is selected to provide active groups, and different cross-linking agents are reacted, the molar ratio of active groups to amino groups is 2:1, and other preparation steps are the same; set up experimental groups 2, 5, 7; measure the gel curing time, rupture strength, swelling rate and subcutaneous implantation reaction of the sealing materials obtained in each example, and the results are shown in Table 3. According to the test results, it is determined that the cross-linking agent is polylysine.

[0094] Table 3 Test results of each group

[0095]

[0096] Experiment three: selection of polylysine

[0097] Selection principle: 4-arm-PEG-SG 20K is selected to provide active groups, and different types of polylysine are reacted, the molar ratio of active groups to amino groups is 2:1, and experimental groups 5 and 6 are set up; the difference between each group is that the form of polylysine as an amino cross-linking agent is different, one is basic polylysine and the other is polylysine hydrochloride. Measure the gel curing time, rupture strength, swelling rate and in vitro degradation of the sealing materials obtained in each example, and the results are shown in Table 4. According to the test results, the performance of the sealing material prepared in experimental group 6 is better than that in experimental group 5, and polylysine hydrochloride is selected as the amino cross-linking agent.

[0098] Table 4 Test results of each group

[0099]

[0100] Experiment four: selection of mixing method

[0101] Selection principle: 4-arm-PEG-SG 20K is selected to provide active groups, polylysine hydrochloride is used as a cross-linking agent, and the molar ratio of active groups to amino groups is 2:1. Experimental groups 6 and 8 are set up; the difference between the two is the mixing method of active ester and cross-linking agent. Measure the gel curing time, rupture strength, swelling rate and in vitro degradation of the sealing materials obtained in each example, and the results are shown in Table 4. The rupture strength and swelling rate of sample 8 are better than those of sample 6, and the in vitro degradation meets the requirements. The mixing method of experimental group 8 is selected.

[0102] Experiment five: selection of alkaline buffer

[0103] Selection principle: 4-arm-PEG-SG 20K is selected to provide active groups, and polylysine hydrochloride is used as a crosslinking agent, the molar ratio of active groups to amino groups is 2:1, 4-arm-PEG-SG 20K is dissolved in a polylysine hydrochloride aqueous solution, and then mixed with different alkaline buffers in equal proportions to set up experiment groups 8, 9 and example 1, the gel curing time, rupture strength, swelling rate, in vitro degradation and cytotoxicity of the obtained sealing materials of each group are determined, and the results are shown in Table 5. According to the test results, the mechanical properties of the adhesive prepared by using sodium bicarbonate buffer alone are inferior to those of the samples prepared by using sodium tetraborate and sodium bicarbonate / sodium carbonate as buffers, but from the perspective of cytotoxicity, sodium bicarbonate / sodium carbonate is better. Therefore, the present application is determined to use 4-arm-PEG-SG 20K to provide active groups, use an acidic polylysine hydrochloride aqueous solution as a crosslinking agent to dissolve the active ester, and use sodium bicarbonate / sodium carbonate buffer as a pH adjuster to form an adhesive with stable performance.

[0104] Table 5 Test results of each group

[0105]

[0106] Experiment six: performance stability test

[0107] The components of groups A and B in example 1 and comparative example 1 are completely the same. In example 1, the mixed system obtained by dissolving 4-arm-PEG-SG in a polylysine hydrochloride aqueous solution is placed for 0 h, 2 h, 6 h and 12 h, and then mixed with a pH adjuster through a nozzle to form a gel, obtaining samples 10-13. In comparative example 1, the A solution is prepared and placed for 0 h, 2 h, 6 h and 12 h, and then mixed with the B solution through a nozzle to form a gel, obtaining samples 14-17. Each sample is repeatedly tested for 10 times, and the rupture strength and in vitro degradation time are determined, and the test results are expressed as mean ± standard deviation (Table 6). The performance stability is evaluated, and it can be seen that the individual differences of the comparative example group are larger, and the A solution cannot be mixed into a gel after being prepared for 2 h.

[0108] Table 6 Test results of each group

[0109]

[0110] The above only describes the preferred embodiments of the present application and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A bioadhesive with stable performance, characterized in that, The raw material composition of the bioadhesive comprises an A component, a B component and a solvent thereof, and a pH regulator; wherein the A component is a multi-arm polyethylene glycol succinimidyl glutarate (n-arm-PEG-SG); The B component is polylysine hydrochloride, and the degree of polymerization of the polylysine hydrochloride is 10-50; and the solvent of the B component is water; The pH regulator is 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 regulator is 9-11; The molar ratio of the active groups of the multi-arm polyethylene glycol succinimidyl glutarate to the amino groups of the polylysine hydrochloride is (1-10):1; The preparation method of the bioadhesive comprises: The B component is dissolved in the solvent of the B component to obtain a solution containing the B component, and then the A component is dissolved in the solution containing the B component to obtain a mixed solution; the mixed solution is mixed with the pH regulator, and then sprayed to obtain the bioadhesive; after the preparation of the mixed solution is completed, the mixed solution can be stored stably at room temperature for not more than 6 hours; and then mixed with the pH regulator.

2. The bioadhesive of claim 1, wherein, The molecular weight of the n-arm-PEG-SG is 10-30K, and n is selected from 4-8.

3. The bioadhesive of claim 2, wherein, The n includes 4, 6 or 8.

4. The bioadhesive according to any of claims 1 to 3, wherein The water is sterile water for injection.

5. Process for the preparation of the bioadhesive of any one of claims 1 to 4, characterized in that, The preparation method comprises: The B component is dissolved in the solvent of the B component to obtain a solution containing the B component, and then the A component is dissolved in the solution containing the B component to obtain a mixed solution; the mixed solution is mixed with the pH regulator, and then sprayed to obtain the bioadhesive; after the preparation of the mixed solution is completed, the mixed solution can be stored stably at room temperature for not more than 6 hours; and then mixed with the pH regulator.

6. A surgical sealant kit characterized by, The surgical sealant kit at least comprises the performance-stable bioadhesive according to any one of claims 1-4.

7. The kit of claim 6, wherein The surgical sealant kit further comprises a double-syringe and an instruction.

8. Use of the bioadhesive according to any one of claims 1-4 or the surgical sealant kit according to any one of claims 6-7 in the preparation of a medical device.

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