Polymer-based medical adhesive as well as preparation method and application thereof

Abstract

The invention relates to a medical adhesive, in particular to a polymer-based medical adhesive as well as a preparation method and application thereof. An intermediate of the polymer-based medical adhesive shown in the formula I and polyethylene glycol react under the action of an activating agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to prepare the polymer-based medical adhesive, and a large number of carboxyl structures in the polymer-based medical adhesive can have electrostatic interaction with amino exposed on the tissue surface; meanwhile, an active ester or benzaldehyde structure can be chemically reacted with amino to form a firm covalent bond; adhesive molecules are cross-linked through polyethylene glycol to enhance the cohesion of the adhesive, so that the polymer-based medical adhesive has a good adhesive effect. Meanwhile, a polyvinylpyrrolidone structure exists in the polymer-based medical adhesive, and the structure has high hydrophilicity and can absorb local moisture; further, the polymer-based medical adhesive still keeps a good adhesion effect in a wet environment.

Description

Technical Field

[0001] The invention relates to a medical adhesive, in particular to a polymer-based medical adhesive and a preparation method and application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the 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] Uncontrolled bleeding caused by damage to internal organs or aorta can pose a serious threat to life. During accidents or cardiovascular surgery, especially when repairing ruptured arteries and hearts, some uncontrolled bleeding often occurs. The lack of rapid and effective means of hemostasis may lead to fatal consequences, such as excessive blood loss or even death. Since the blood pressure in the heart and arteries is usually high, even the commonly used surgical closure techniques in surgery (such as needle and thread suturing, closure nails and electrocautery) usually cannot completely block arterial and cardiac bleeding, and these operations are not feasible in emergency situations. Therefore, there is a huge clinical demand for the development of medical tissue adhesives that can be used for rapid hemostasis and healing of internal organs.

[0004] Since the 1950s, scientists have begun to develop tissue adhesives as a substitute for sutures / staples. Ideal tissue adhesives should have the following properties: 1) strong adhesion; 2) wet adhesion; 3) biodegradable; 4) ductile; 5) good biosafety (low cytotoxicity and inflammatory stimulation).

[0005] Commercial tissue adhesives currently available on the market have greatly facilitated surgical operations. For example, fibrin glue, bovine serum albumin-glutaraldehyde glue (Bioglue) and cyanoacrylate are all commercial tissue adhesives that can help simplify surgical operations. However, these commercial tissue adhesives are not ideal tissue adhesives that can be used in vivo. Fibrin glue is the only medical adhesive that can be used to seal visceral tissues; however, it has low adhesion to tissues and organs in a wet environment, making it difficult to achieve rapid adhesion and hemostasis of wet visceral tissues and organs, especially for massive bleeding in arteries, heart and other tissues, and the use and operation process is complicated, and may cause viral infection and allergic reactions. Bioglue and cyanoacrylate have strong tissue adhesion, but their wet adhesion effect is still poor, and their non-biocompatibility (having aldehyde components or exudates) and non-biodegradability may lead to excessive inflammatory responses in the host. Therefore, the development of medical tissue adhesives that can be used for visceral organ adhesion and hemostasis to achieve effective hemostasis of arteries and viscera remains an urgent and severe clinical challenge. Summary of the invention

[0006] In order to overcome the above problems, the present invention provides a polymer-based medical adhesive and a preparation method and application thereof.

[0007] In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

[0008] In the first aspect of the present invention, there is provided an intermediate of a polymer-based medical adhesive, the structural formula of which is shown in Formula I:

[0009]

[0010] Wherein, m is an integer of 40 to 60, n is an integer of 20 to 30, p is an integer of 20 to 30, and m=n+p;

[0011] In Formula I, the R group is selected from the following structures:

[0012]

[0013] The second aspect of the present invention provides a method for preparing an intermediate of a polymer-based medical adhesive, comprising:

[0014] (1) synthesizing the intermediate precursor VA of the polymer-based medical adhesive by vinyl pyrrolidone and acrylic acid under the initiation of an initiator;

[0015] (2) the intermediate precursor VA and the active molecule are polymerized under the action of an activator to form an intermediate of a polymer-based medical adhesive represented by formula I;

[0016] Synthesis route:

[0017]

[0018] Wherein, j is an integer of 40 to 60, k is an integer of 40 to 60, and j=k; the limiting conditions of the intermediate of the polymer-based medical adhesive represented by formula I are the same as those of the first aspect.

[0019] In one or more embodiments, the molar ratio of vinyl pyrrolidone to acrylic acid is 0.8-1.2:0.8-1.2, preferably 1:1.

[0020] In one or more embodiments, the solvent used in the polymerization reaction in steps (1) and (2) is selected from one of N,N-dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran and toluene, preferably N,N-dimethylformamide.

[0021] In one or more embodiments, the initiator is selected from one of azobisisobutyronitrile (AIBN), dimethyl azobisisobutyrate, azobisisoheptanenitrile, benzoyl peroxide, tert-butyl benzoyl peroxide and methyl ethyl ketone peroxide, preferably azobisisobutyronitrile.

[0022] In one or more embodiments, when synthesizing the intermediate precursor VA, the reaction temperature is 70 to 90° C., preferably 80° C.; the reaction time is 60 to 80 hours, preferably 72 hours.

[0023] In one or more embodiments, the active molecule is selected from one of N-hydroxysuccinimide, sodium salt of N-hydroxysuccinimide sulfonate, p-hydroxybenzaldehyde, p-hydroxymethylbenzaldehyde and pentafluorophenol, preferably one of N-hydroxysuccinimide and p-hydroxybenzaldehyde.

[0024] In one or more embodiments, the activator is selected from one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dicyclohexylcarbodiimide and diisopropylcarbodiimide, preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

[0025] In one or more embodiments, when synthesizing the intermediate of the polymer-based medical adhesive represented by Formula I, the mass ratio of the intermediate precursor VA to the activator and the active molecule is: 3.6:1.8-2.0:1.1-1.2.

[0026] In one or more embodiments, when synthesizing the intermediate of the polymer-based medical adhesive of Formula I, the catalyst includes 4-dimethylaminopyridine (DMAP).

[0027] In one or more embodiments, when synthesizing the intermediate of the polymer-based medical adhesive represented by Formula I, the reaction conditions are stirring reaction at room temperature, and the reaction time is 40 to 60 hours, preferably 48 hours.

[0028] The third aspect of the present invention provides a polymer-based medical adhesive, which is prepared by an intermediate of the polymer-based medical adhesive shown in Formula I and a cross-linking agent under the action of an activator, wherein the mass ratio of the intermediate of the polymer-based medical adhesive shown in Formula I, the activator and the cross-linking agent is 25:0.5~2:1~4; the reaction conditions are stirring the reaction at room temperature, and the reaction time is 20~30h; the catalyst includes 4-dimethylaminopyridine.

[0029] In one or more embodiments, the activator is selected from one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dicyclohexylcarbodiimide and diisopropylcarbodiimide, preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

[0030] In one or more embodiments, the cross-linking agent is selected from one of polyethylene glycol, polyglycerol and polyvinyl alcohol, preferably polyethylene glycol.

[0031] Preferably, the mass ratio of the intermediate of the polymer-based medical adhesive represented by Formula I to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and polyethylene glycol is 25:1:2.

[0032] In one or more embodiments, the reaction is carried out under stirring at room temperature for 24 hours.

[0033] Preferably, the viscosity of the polymer-based medical adhesive in dichloromethane / ethanol (volume ratio of 5:2) is 200 to 400 mPa·s.

[0034] The fourth aspect of the present invention provides a method for preparing the polymer-based medical adhesive according to the third aspect, comprising:

[0035] The intermediate and cross-linking agent of the polymer-based medical adhesive shown in formula I are prepared under the action of an activator, wherein the mass ratio of the intermediate, activator and cross-linking agent of the polymer-based medical adhesive shown in formula I is 25:0.5-2:1-4; the reaction conditions are stirring reaction at room temperature, and the reaction time is 20-30 hours; the catalyst includes 4-dimethylaminopyridine.

[0036] The fifth aspect of the present invention provides the use of the above polymer-based medical adhesive in the preparation of products for wound adhesion, hemostasis, visceral and soft tissue wound closure, covering, plugging, and hard tissue fixation.

[0037] A sixth aspect of the present invention provides a medical adhesive comprising the above polymer-based medical adhesive.

[0038] In one or more embodiments, the medical adhesive further comprises one or more adjuvants, the adjuvants being selected from thickeners, stabilizers, heat and / or light initiators and accelerators for initiating crosslinking, colorants, plasticizers, preservatives, heat dissipators, biocompatible agents, and fiber reinforcements; further, one or more biological agents or therapeutic agents are also included, wherein the plasticizer includes but is not limited to polyethylene glycol esters, blocked polyesters, butyl stearate, lauric acid, dioctyl glutarate, triglycerides, dioctyl oxalate, triethyl phosphate, and acetyl tri-citrate;

[0039] Wherein, thickeners include but are not limited to polycyanoacrylate, polylactic acid, polyglycolic acid, polycaprolactone, polyalkyl acrylate, polyalkyl methacrylate;

[0040] Preservatives include, but are not limited to, preservatives that are conventionally used but do not induce polymerization of monomers, selected from potassium sorbate, sodium benzoate, sorbic acid, chlorocresol;

[0041] The heat dissipating agent includes a liquid miscible with the monomer, which can evaporate during polymerization to release heat from the composition. Suitable heat dissipating agents are disclosed in U.S. Pat. No. 6,010,714, the entire disclosure of which is incorporated herein by reference;

[0042] Fiber reinforcement materials include but are not limited to natural rubber or synthetic rubber to enhance the impact resistance of the composition, such as styrene, acrylonitrile, etc.;

[0043] Stabilizers include anionic stabilizers and free radical stabilizers. The former include metaphosphoric acid, maleic acid, maleic anhydride, alkyl sulfonic acid, phosphorus pentoxide, iron (III) chloride, antimony oxide, 2,4,6-trinitrophenol mercaptan, alkyl sulfonyl, alkyl sulfone, alkyl sulfoxide, alkyl sulfite, sultone, sulfur dioxide and sulfur trioxide, etc.; the latter include hydroquinone, catechol and derivatives of the above compounds;

[0044] Colorants are selected from dyes and pigments, including PGA microfibrils, collagen microfibrils, cellulose microfibrils and olefinic microfibrils; biological agents or therapeutic agents include but are not limited to anti-inflammatory analgesics, sedatives, local anesthetics, non-steroidal anti-inflammatory drugs, antiallergic drugs, antiulcer drugs, antibiotics, antibacterial drugs, antiviral drugs, antifungal drugs, immunosuppressants, naturally derived proteins or genetically engineered proteins, polysaccharides, glycoproteins or ester proteins, oligonucleotides, polypeptide drugs, antibodies, antigens, chemotherapeutic drugs, procoagulants and hemostatic agents, such as prothrombin, thrombin, fibrinogen, fibrin, adhesion proteins, coagulation factors, tissue factors, collagen, gelatin, vasopressin, plasminogen activator inhibitors, platelet activators and synthetic peptides with hemostatic activity; biocompatible agents include but are not limited to sodium bisulfite;

[0045] Polymerization initiators or promoters include but are not limited to: molecules with nucleophilic functional groups, organic or inorganic or mixtures thereof, selected from amino, quaternary amine, hydroxyl, thiol, phosphorus-containing compounds, specifically NaHCO3, Na2CO3, sodium phosphate.

[0046] The beneficial effects of the present invention are:

[0047] (1) The intermediate of the polymer-based medical adhesive shown in Formula I reacts with polyethylene glycol under the action of the activator 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to obtain a polymer-based medical adhesive molecule. A large number of carboxyl structures in the polymer-based medical adhesive can have electrostatic interactions with the amino groups exposed on the tissue surface, and the active ester or benzaldehyde structure can react chemically with the amino groups to form a strong covalent bond; the adhesive molecules are cross-linked by polyethylene glycol to enhance the cohesive force of the adhesive, so that the polymer-based medical adhesive provided by the present invention has a good bonding effect. At the same time, there is a polyvinyl pyrrolidone structure in the polymer-based medical adhesive, which has a strong hydrophilicity and can absorb local moisture; thereby, the polymer-based medical adhesive still maintains a good bonding effect in a wet environment. Furthermore, the polymer-based medical adhesive provided by the present invention has good biocompatibility, so the polymer-based medical adhesive provided by the present invention can be used to prepare products for wound bonding, hemostasis, visceral and soft tissue wound closure, covering, plugging, and hard tissue fixation.

[0048] (2) The polymer-based medical adhesive provided by the present invention has a simple and convenient synthesis method, high yield, and is easy to prepare, and is suitable for scale-up synthesis and actual production application. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0050] Figure 1 is the H NMR spectrum of the intermediate precursor VA;

[0051] Figure 2 The results of the carboxyl content in the intermediate precursor VA were determined by NaOH titration experiment;

[0052] Figure 3 To detect the molecular weight and molecular weight distribution of the intermediate precursor VA, the intermediate VAN of the polymer-based medical adhesive and the intermediate VAB of the polymer-based medical adhesive by gel permeation chromatography;

[0053] Figure 4 This is the H-NMR spectrum of VAN, an intermediate of polymer-based medical adhesives;

[0054] Figure 5 This is the H-NMR spectrum of VAB, an intermediate of polymer-based medical adhesives;

[0055] Figure 6 The results of the QCMD test of the reaction activity of intermediates VAN and VAB with amino groups;

[0056] Figure 7 The infrared spectra of polymer-based medical adhesives VANP and VABP;

[0057] Figure 8 A test procedure for evaluating adhesion strength by lap-shear tensile bearing strength testing;

[0058] Fig. 9 To evaluate the test results of adhesion strength by lap-shear tensile bearing strength test;

[0059] Fig.10 This is the CCK8 test result;

[0060] Fig.11 Results of cell live-death staining experiments;

[0061] Fig.12 The adhesion effect of polymer-based medical adhesive VANP on different organs (kidney, spleen, heart) of rats;

[0062] Fig.13 The adhesion effect of polymer-based medical adhesive VABP on different organs (kidney, spleen, heart) of rats. DETAILED DESCRIPTION

[0063] It should be noted that the following detailed descriptions are exemplary and are 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.

[0064] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0065] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0066] Example 1

[0067] Synthetic intermediate precursor VA

[0068] In a round-bottom flask, 11.1 g of vinyl pyrrolidone (NVP, CAS No.: 88-12-0, purchased from McLean), 7.2 g of acrylic acid (AAc, CAS No.: 79-10-7, purchased from McLean) and 1 mol% of azobisisobutyronitrile (AIBN, CAS No.: 78-67-1, purchased from McLean) were dissolved in DMF (200 mL). After high-purity nitrogen was introduced for 30 minutes, the flask was sealed with a rubber stopper, placed in an oil bath pot, heated (80°C), and stirred for 72 hours. After the reaction was completed, the reaction mixture was poured into (1000 mL) of anhydrous ether, the supernatant was removed, and the flask was washed with anhydrous ether for 2 to 3 times, and then dried in a vacuum environment for 24 hours to obtain the intermediate precursor VA.

[0069] Synthesis route:

[0070]

[0071] The molecular structure of the intermediate precursor VA was characterized by H NMR spectroscopy, the solvent was DMSO-d6, and the results were as follows Figure 1 As shown. After integral calculation, the ratio of the number of repeating units of the two monomers is 1:1.

[0072] The carboxyl content in the intermediate precursor VA was determined by NaOH titration experiment. The results are as follows Figure 2 As shown, after calculation, the total carboxyl content in the polymer is 0.1 mmol.

[0073] The molecular weight and molecular weight distribution of the intermediate precursor VA were detected by gel permeation chromatography, with DMF as the mobile phase and a flow rate of 1 mL / min. Figure 3 And as shown in Table 1.

[0074] Finally, the structural formula of the intermediate precursor VA is as follows:

[0075]

[0076] Example 2

[0077] Intermediates for the synthesis of polymer-based medical adhesives

[0078] In a round-bottom flask, 3.6 g of VA was dissolved in 50 mL of DMF, and 1.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, CAS No.: 25952-53-8, purchased from McLean) was added, and stirred for 1 h to obtain a clear solution. 1.15 g of N-hydroxysuccinimide (NHS, CAS No.: 6066-82-6, purchased from McLean) was weighed and added to the mixed solution, and 0.01 g of 4-dimethylaminopyridine (DMAP, CAS No.: 1122-58-3, purchased from McLean) was added, and the reaction was continued at room temperature for 48 h. After the reaction was completed, the reaction mixture was poured into (500 mL) of anhydrous ether, the supernatant was removed, and the mixture was washed with anhydrous ether for 2 to 3 times, and then dried in a vacuum environment for 24 h to obtain the intermediate VAN of the polymer-based medical adhesive.

[0079] The specific process of the reaction includes:

[0080]

[0081] The H NMR spectrum of the intermediate VAN is as follows Figure 4 As shown, after integral calculation, the NHS modification rate is about 53%.

[0082] The molecular weight and molecular weight distribution of the intermediate VAN were detected by gel permeation chromatography, with DMF as the mobile phase and a flow rate of 1 mL / min. Figure 3 And as shown in Table 1.

[0083] Finally, the structural formula of the intermediate VAN is as follows:

[0084]

[0085] Example 3

[0086] Intermediates for the synthesis of polymer-based medical adhesives:

[0087] In a round-bottom flask, 3.6 g of VA was dissolved in 50 mL of DMF, and 1.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, CAS No.: 25952-53-8, purchased from McLean) was added, and the mixture was stirred for 1 h to obtain a clear solution. 1.22 g of p-hydroxybenzaldehyde (BA, CAS No.: 123-08-0, purchased from McLean) was weighed and added to the mixed solution, and 0.01 g of 4-dimethylaminopyridine (DMAP, CAS No.: 1122-58-3, purchased from McLean) was added, and the reaction was continued at room temperature for 48 h. After the reaction was completed, the reaction mixture was poured into (500 mL) of anhydrous ether, the supernatant was removed, and the mixture was washed with anhydrous ether for 2 to 3 times, and then dried in a vacuum environment for 24 h to obtain the intermediate VAB of the polymer-based medical adhesive shown in Formula II.

[0088] The specific process of the reaction includes:

[0089]

[0090] The H NMR spectrum of the intermediate VAB is as follows Figure 5 As shown, after integral calculation, the BA modification rate is about 56%.

[0091] The molecular weight and molecular weight distribution of the intermediate VAB were detected by gel permeation chromatography with DMF as the mobile phase and a flow rate of 1 mL / min. Figure 3 And as shown in Table 1.

[0092] Finally, the structural formula of the intermediate VAB is as follows:

[0093]

[0094] Table 1 Molecular weight of each polymer in Examples 1 to 3

[0095]

[0096] Example 4

[0097] Dissipative quartz crystal microbalance (QCMD) was used to test the reactivity of intermediates VAN and VAB with amino groups:

[0098] In a 37°C environment, first slowly pass a polyethyleneimine (PEI, CAS No.: 9002-98-6, purchased from McLean) solution (2 mg / mL) into the QCMD flow cell at a flow rate of 0.1 mL / mL. After adsorption equilibrium, rinse off the unadsorbed PEI molecules with PBS. Then pass different polymer solutions (2 mg / mL) and observe the changes in the chip vibration frequency. The adsorption amount of the polymer on the PEI coating surface can be calculated by software fitting.

[0099] The results are as follows Figure 6 As shown, it can be seen from the figure that the intermediates VAN and VAB have high reactivity with amino groups, and VAB has higher reactivity with amino groups.

[0100] Example 5

[0101] Synthetic polymer-based medical adhesives:

[0102] In a round-bottom flask, 2.5 g of VAN was dissolved in 50 mL of DMF, and 0.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, CAS No.: 25952-53-8, purchased from McLean) was added, and stirred for 1 h to obtain a clear solution. 0.2 g of polyethylene glycol (PEG, CAS No.: 25322-68-3, purchased from McLean) was weighed and added to the mixed solution, and 0.001 g of 4-dimethylaminopyridine (DMAP, CAS No.: 1122-58-3, purchased from McLean) was added as a catalyst, and the reaction was continued at room temperature for 24 h. After the reaction was completed, the reaction mixture was poured into (500 mL) of anhydrous ether, the supernatant was removed, and the mixture was washed with anhydrous ether for 2 to 3 times, and then dried in a vacuum environment for 24 h to obtain a polymer-based medical adhesive VANP, which appeared as a light yellow solid.

[0103]

[0104] VAN contains multiple carboxyl groups (-COOH). EDC, as a coupling agent, first activates the carboxyl groups (-COOH) in VAN. The activated carboxyl groups react with the hydroxyl groups (-OH) of PEG to form ester bonds (-COO-), thereby connecting PEG to the polymer chain. The infrared spectrum of the product is shown in Figure 2. Figure 7 As shown, the characteristic peaks of PEG can be observed from the figure, proving the successful introduction of the PEG component.

[0105] Example 6

[0106] Synthetic polymer-based medical adhesives:

[0107] In a round-bottom flask, 2.5 g of VAB was dissolved in 50 mL of DMF, and 0.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, CAS No.: 25952-53-8, purchased from McLean) was added, and stirred for 1 h to obtain a clear solution. 0.2 g of polyethylene glycol 400 (PEG, CAS No.: 25322-68-3, purchased from McLean) was weighed and added to the mixed solution, and 0.001 g of 4-dimethylaminopyridine (DMAP, CAS No.: 1122-58-3, purchased from McLean) was added as a catalyst, and the reaction was continued at room temperature for 24 h. After the reaction was completed, the reaction mixture was poured into (500 mL) of anhydrous ether, the supernatant was removed, and the mixture was washed with anhydrous ether for 2 to 3 times, and then dried in a vacuum environment for 24 h to obtain a polymer-based medical adhesive VABP, which appeared to be a light yellow solid.

[0108]

[0109] VAB contains multiple carboxyl groups (-COOH). EDC, as a coupling agent, first activates the carboxyl groups (-COOH) in VAB. The activated carboxyl groups then react with the hydroxyl groups (-OH) of PEG to form ester bonds (-COO-), thereby connecting PEG to the polymer chain. The infrared spectrum of the product is shown in Figure 2. Figure 7 As shown, the characteristic peaks of PEG can be observed from the figure, proving the successful introduction of the PEG component.

[0110] Example 7

[0111] Preparation of polymer-based medical adhesive patches

[0112] The polymer-based medical adhesive VANP or VABP is dispersed in a mixed solvent of dichloromethane / methanol (volume ratio of 5:2) at a concentration of 300 mg / mL. The solution is coated on the surface of the release paper using a coating rod, and after the solvent evaporates completely, a polymer-based medical adhesive film with a thickness of 50 μm is obtained. The film is then removed and cut into appropriate sizes to obtain a polymer-based medical adhesive patch.

[0113] Example 8

[0114] Evaluating adhesion strength through lap-shear tensile bearing strength testing

[0115] Take pig skin (2.0cm×2.5cm) with the fat removed, and stick the polymer-based medical adhesive patch on the overlapping area between the two pieces of pig skin. Apply a certain force (200N) to the bonding area and keep it for 1 minute to bond the two pieces of pig skin tissue together. Place the pig skin sample in the fixture so that the force direction is the long axis direction of the sample, and load the sample at a speed of 5mm / min until it is destroyed. Measure and record the width and length of the bonding area, record the load and calculate the bonding strength. The specific test process is as follows: Figure 8 As shown, the results are Fig. 9 As shown in the figure, both polymer-based medical adhesive patches have good adhesion strength, and the adhesion strengths of VANP and VABP are 0.069±0.012MPa and 0.108±0.038MPa, respectively.

[0116] Example 9

[0117] In vitro cell experiments

[0118] CCK8 test: 3T3 cells were seeded in 96-well culture plates at a concentration of 8 × 10 3 After culturing in the incubator for 12 hours, the old culture medium was removed and replaced with a culture medium solution containing different concentrations of adhesive extract. After being placed back in the CO2 incubator for another 24 hours, 10 μL of CCK8 solution was added to each well and cultured for another 4 hours. Finally, the culture plate was scanned using an ELISA reader with a detection wavelength of 450 nm.

[0119] Cell live-death staining experiment: 3T3 cells were seeded in a 6-well culture plate at a seeding density of 2×10 6 Cells / well. After incubation in a carbon dioxide incubator for 12 hours, the old culture medium was removed and replaced with a culture medium solution containing different concentrations of adhesive extracts. After culturing for 24 hours, the culture medium was removed and fluorescent dyes (calcein and propidium iodide) were added and cultured for 10 minutes for staining. Finally, an inverted fluorescence microscope was used for observation and photography.

[0120] CCK8 test results Fig.10 As shown in the figure, it can be seen that both VANP and VABP showed negligible cytotoxicity levels, indicating excellent biocompatibility.

[0121] The results of cell live-death staining experiments are as follows Fig.11 As shown, the cells were stained with calcein and propidium iodide and observed under a fluorescent inverted microscope, with live cells shown in green and dead cells in red. The results showed that no obvious red signal was found in the figure, indicating that both polymer-based medical adhesives were not toxic to cells and showed high biocompatibility.

[0122] Example 10

[0123] The polymer-based medical adhesive VANP or VABP is used for tissue adhesion, and the adhesion effect is as follows Fig.12 and Fig.13 As shown in the figure, VANP or VABP has adhesion to different organs of rats (such as kidney, spleen, heart), and can achieve good underwater adhesion effect.

[0124] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. An intermediate of a polymer-based medical adhesive, characterized in that: Its structural formula is shown in Formula I. Wherein, m is an integer of 40 to 60, n is an integer of 20 to 30, p is an integer of 20 to 30, and m=n+p; In Formula I, the R group is selected from the following structures:

2. The method for preparing the intermediate of the polymer-based medical adhesive according to claim 1, characterized in that: include: (1) synthesizing the intermediate precursor VA of the polymer-based medical adhesive by vinyl pyrrolidone and acrylic acid under the initiation of an initiator; (2) the intermediate precursor VA and the active molecule are polymerized under the action of an activator to form an intermediate of a polymer-based medical adhesive represented by formula I; Synthesis route: Wherein, j is an integer of 40 to 60, k is an integer of 40 to 60, and j=k; the limiting conditions of the intermediate of the polymer-based medical adhesive represented by formula I are the same as those defined in claim 1.

3. The preparation method according to claim 2, characterized in that: The molar ratio of vinyl pyrrolidone to acrylic acid is 0.8-1.2:0.8-1.2, preferably 1:1; Or, the solvent used in the polymerization reaction in steps (1) and (2) is selected from one of N,N-dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran and toluene, preferably N,N-dimethylformamide; Or, the initiator is one selected from azobisisobutyronitrile (AIBN), dimethyl azobisisobutyrate, azobisisoheptanenitrile, benzoyl peroxide, tert-butyl benzoyl peroxide and methyl ethyl ketone peroxide, preferably azobisisobutyronitrile; Or, when synthesizing the intermediate precursor VA, the reaction temperature is 70-90° C., preferably 80° C.; the reaction time is 60-80 h, preferably 72 h.

4. The preparation method according to claim 2, characterized in that: The active molecule is selected from one of N-hydroxysuccinimide, sodium salt of N-hydroxysuccinimide sulfonate, p-hydroxybenzaldehyde, p-hydroxymethylbenzaldehyde and pentafluorophenol, preferably one of N-hydroxysuccinimide and p-hydroxybenzaldehyde; Or, the activator is selected from one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dicyclohexylcarbodiimide and diisopropylcarbodiimide, preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; Or, when synthesizing the intermediate of the polymer-based medical adhesive represented by formula I, the mass ratio of the intermediate precursor VA to the activator and the active molecule is: 3.6:1.8-2.0:1.1-1.2; Or, when synthesizing the intermediate of the polymer-based medical adhesive represented by formula I, the catalyst includes 4-dimethylaminopyridine; Or, when synthesizing the intermediate of the polymer-based medical adhesive represented by formula I, the reaction conditions are stirring reaction at room temperature, and the reaction time is 40 to 60 hours, preferably 48 hours.

5. A polymer-based medical adhesive, characterized in that: The polymer-based medical adhesive is prepared by an intermediate of the polymer-based medical adhesive shown in formula I and a cross-linking agent under the action of an activator, wherein the mass ratio of the intermediate of the polymer-based medical adhesive shown in formula I, the activator and the cross-linking agent is 25:0.5-2:1-4; the reaction conditions are stirring reaction at room temperature, and the reaction time is 20-30 hours; the catalyst includes 4-dimethylaminopyridine.

6. The polymer-based medical adhesive according to claim 5, characterized in that The activator is selected from one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dicyclohexylcarbodiimide and diisopropylcarbodiimide, preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; Or, the cross-linking agent is selected from one of polyethylene glycol, polyglycerol and polyvinyl alcohol, preferably polyethylene glycol; Preferably, the mass ratio of the intermediate of the polymer-based medical adhesive represented by Formula I to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and polyethylene glycol is 25:1:2; Or, the reaction conditions are stirring the reaction at room temperature and the reaction time is 24h; Alternatively, the polymer-based medical adhesive has a viscosity of 200 to 400 mPa·s in dichloromethane / ethanol (volume ratio of 5:2).

7. The method for preparing the polymer-based medical adhesive according to claim 5, characterized in that: include: The intermediate and cross-linking agent of the polymer-based medical adhesive shown in formula I are prepared under the action of an activator, wherein the mass ratio of the intermediate, activator and cross-linking agent of the polymer-based medical adhesive shown in formula I is 25:0.5-2:1-4; the reaction conditions are stirring reaction at room temperature, and the reaction time is 20-30 hours; the catalyst includes 4-dimethylaminopyridine.

8. Use of the polymer-based medical adhesive of claim 5 in the preparation of products for wound adhesion, hemostasis, visceral and soft tissue wound closure, covering, plugging, and hard tissue fixation.

9. A medical adhesive, characterized in that: The invention comprises the polymer-based medical adhesive as claimed in claim 5.

10. The medical adhesive according to claim 9, characterized in that The medical adhesive further comprises one or more adjuvants, which are selected from thickeners, stabilizers, heat and / or light initiators and accelerators for initiating crosslinking, colorants, plasticizers, preservatives, heat dissipating agents, biocompatible agents, and fiber reinforcement materials.

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