Vein closure adhesive as well as preparation method and application thereof

Abstract

The invention relates to a vein closure adhesive as well as a preparation method and application thereof, the vein closure adhesive is prepared by reaction of raw materials, and the raw materials comprise a cyanoacrylate monomer, a PMMA modifier, a polymerization inhibitor, a stabilizer and an antioxidant; wherein the feeding mass ratio of the PMMA modifier is 5%-25% of that of the cyanoacrylate monomer; the feeding mass ratio of the polymerization inhibitor to the cyanoacrylate monomer is 0.002%-0.01%; the feeding mass ratio of the stabilizer is 0.005%-0.1% of that of the cyanoacrylate monomer; the feeding mass ratio of the antioxidant is 0.02%-0.06% of that of the cyanoacrylate monomer. During preparation, the cyanoacrylate monomer is uniformly mixed with the polymerization inhibitor, the stabilizer, the antioxidant and the PMMA modifier to prepare the vein closure adhesive. By designing a brand new preparation route of the vein closure adhesive, the barrier that a cyanoacrylate adhesive needs to be synthesized by formaldehyde is broken through, the problem that in-vivo application of aldehyde-containing glue is limited is solved, and the vein closure adhesive is suitable for treating varicosity.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a vein closing adhesive and a preparation method and application thereof. Background Art

[0002] Varicose veins are mainly caused by chronic inflammation and blood flow disorders, among which varicose veins in the lower extremities are the most common. As the disease progresses, the patient's symptoms such as leg soreness, heaviness, pain, and cramps become more and more severe. In extreme cases, blood clots may form in the veins, causing pulmonary embolism in severe cases, threatening the patient's life.

[0004] At present, the treatments for varicose veins include traditional high vein ligation (stripping varicose veins), thermal ablation and sclerosant injection. Traditional vein stripping requires an open surgical incision, and the surgical trauma is large, causing certain damage to surrounding tissues and nerves, and the postoperative repair period is long. The principle of thermal ablation is to achieve the treatment purpose by thermally stimulating the contraction and occlusion of vascular endothelial fibrosis. This treatment method is very likely to cause complications such as surrounding tissue burns, venous splitting, and subcutaneous swelling. At the same time, long-term elastic stockings are required for treatment after surgery. Postoperative care requirements are high and often accompanied by recurrence. It is reported that the 5-year recurrence rate is as high as 30%. Sclerosant injection therapy mainly injects sclerosants into blood vessels to stimulate the vein wall, causing fibrosis to achieve closure. This treatment method is only suitable for patients with mild varicose veins. The treatment cycle is as long as 6 months or more and the recurrence rate is high (the recurrence rate is more than 50%). It is gradually used as an auxiliary treatment for ablation.

[0005] In recent years, a new method of using adhesive bonding technology to treat varicose veins has been proposed. This method achieves the purpose of eliminating reflux by injecting adhesive (α-cyanoacrylate) into the venous cavity to bond the venous lumen together. This treatment method has the advantages of quick operation, no need for anesthesia, almost non-invasive surgery, low recurrence rate, suitable for outpatient surgery and no need for hospitalization. However, the cyanoacrylates currently under development all use formaldehyde as a raw material, and formaldehyde is a harmful substance and has three-cause effects, which limits its application in the body. Secondly, the viscosity of cyanoacrylate is low, and it is easy to flow to other parts with the blood when solidifying, causing ectopic embolism. However, there are still no related products on the market in China regarding the use of adhesives to treat varicose veins. Summary of the invention

[0006] The purpose of the present invention is to provide a vein closure adhesive and a preparation method and application thereof, which solves the problem of poor compliance of cyanoacrylate adhesives in the prior art and ectopic embolism during curing due to low viscosity, and aims to achieve the purpose of treating varicose veins by bonding veins together using formaldehyde-free adhesive bonding technology.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is:

[0008] The first aspect of the present invention provides a vein closure adhesive, which is made by reacting raw materials, wherein the raw materials include: a cyanoacrylate monomer, a PMMA modifier, an inhibitor, a stabilizer and an antioxidant;

[0009] Wherein, the feed mass ratio of the PMMA modifier is 5%-25% of the cyanoacrylate monomer;

[0010] The mass ratio of the polymerization inhibitor is 0.002%-0.01% of the cyanoacrylate monomer;

[0011] The feed mass ratio of the stabilizer is 0.005%-0.1% of the cyanoacrylate monomer;

[0012] The feeding mass ratio of the antioxidant is 0.02%-0.06% of the cyanoacrylate monomer.

[0013] Furthermore, the cyanoacrylate monomer is prepared by reacting active methylene ester and cyanoacetate under the action of an organic salt catalyst, and the molar ratio of the active methylene ester, the cyanoacetate and the organic salt catalyst is (1.2-1.5):(0.9-1.1):(0.005-0.01).

[0014] Furthermore, the cyanoacetate is a mixture of one or more selected from methyl cyanoacetate, ethyl cyanoacetate, n-butyl cyanoacetate, isobutyl cyanoacetate, n-pentyl cyanoacetate, n-octyl cyanoacetate, isooctyl cyanoacetate and sec-octyl cyanoacetate.

[0015] Furthermore, the active methylene ester is prepared by reacting a halogenated alkane / active methylene substance and an acid anhydride under the action of a quaternary ammonium salt catalyst, and the molar ratio of the halogenated alkane / active methylene substance, the acid anhydride and the quaternary ammonium salt catalyst is (0.5-1):1:(0.005-0.01).

[0016] Furthermore, the halogenated alkane is a mixture of one or more selected from dichloromethane, dibromomethane and diiodomethane; the active methylene substance is a polyaldehyde substance or a polyketone substance; the acid anhydride substance is a mixture of one or more selected from formic anhydride, acetic anhydride, caproic anhydride, ethylpropionic anhydride and maleic anhydride.

[0017] Furthermore, the PMMA modifier is prepared by reacting modified SiO2 and acrylate substances under the action of an initiator.

[0018] Further, the modified SiO2 is a mixture of one or more selected from SiO2-γ-methacryloxypropyltrimethoxysilane, SiO2-methylpropylmethacryloxypropyltrimethoxysilane, SiO2-vinyltriethoxysilane and SiO2-vinyltri(β-methoxyethoxy)silane;

[0019] The acrylic acid ester substance is a mixture of one or more selected from methyl methacrylate, ethyl methacrylate, ethyl acrylate and hydroxyethyl methacrylate.

[0020] Furthermore, the inhibitor is a mixture of one or more selected from sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, dodecylbenzenesulfonic acid and sulfur dioxide; the stabilizer is a mixture of one or more selected from phenol, hydroquinone, thiobisphenol and catechol; the antioxidant is a mixture of one or more selected from butylated hydroxyanisole, p-propenylanisole and hydroxyanisole.

[0021] A second aspect of the present invention provides a method for preparing a vein closure adhesive, comprising the following steps:

[0022] (1) Mixing halogenated alkane or active methylene substances with acid anhydrides and quaternary ammonium salt catalysts and heating at 65 to 85° C. for 3.5 to 4.5 hours to prepare active methylene esters;

[0023] (2) mixing the active methylene ester with cyanoacetate and an organic salt catalyst at 120 to 160° C. and heating for 3 to 7 hours to obtain a cyanoacrylate monomer;

[0024] (3) mixing the modified SiO2 with an acrylate substance and an initiator for reaction, and then post-treating to obtain a PMMA modifier;

[0025] (4) The cyanoacrylate monomer is uniformly mixed with an inhibitor, a stabilizer, an antioxidant and the PMMA modifier to prepare the vein closure adhesive.

[0026] Furthermore, the quaternary ammonium salt catalyst in step (1) is a mixture of one or more selected from methacryloyloxyethyl trimethyl ammonium chloride, trimethyl benzyl ammonium chloride and hexadecyl benzyl dimethyl ammonium chloride.

[0027] Furthermore, the organic salt catalyst in step (2) is prepared by reacting an organic acid and an organic base;

[0028] The organic acid is a mixture of one or more selected from formic acid, acetic acid, butyric acid, methanesulfonic acid, p-toluenesulfonic acid, o-toluenesulfonic acid and dodecylbenzenesulfonic acid; the organic base is a mixture of one or more selected from methylamine, ethylamine, 3-methylpyridine, 2-methylpiperidine, 2-methylpiperazine, aminoethylpiperazine and N-methylpiperazine.

[0029] Furthermore, the initiator in step (3) is potassium persulfate or ammonium persulfate.

[0030] A third aspect of the present invention provides a use of a vein-sealing adhesive, wherein the vein-sealing adhesive can be used to treat varicose veins.

[0031] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0032] The present invention utilizes the characteristic of cyanoacrylate that it can quickly close varicose veins, and completely designs the preparation route of cyanoacrylate. At the same time, a PMMA modifier is integrated to improve the viscosity and compliance of the adhesive. The prepared vein closing adhesive has good biocompatibility, realizes a formaldehyde-free preparation process, and avoids the risk of ectopic embolism caused by the adhesive. DETAILED DESCRIPTION

[0034] Embodiment 1:

[0035] This embodiment provides a vein closure adhesive and a preparation method thereof, comprising the following steps:

[0036] (1) 894 g of dichloromethane and 1362.2 g of acetic anhydride were added to a three-necked flask, and then 40.4 g of hexadecylbenzyldimethylammonium chloride was added. The atmosphere was replaced with nitrogen for more than three times, and the reaction was carried out at 75° C. for 4 h to obtain a crude product of methylene diacetate;

[0037] Then, the crude methylene diacetate was placed in a distillation tower for distillation (the reflux ratio was controlled at 4:1), and 2469.05 g of pure methylene diacetate was obtained at a tower top temperature of 90°C.

[0038] (2) 237.5 g of the above-mentioned methylene diacetate and 181.26 g of n-butyl cyanoacetate were added to a three-necked flask, and 2.83 g of p-toluenesulfonic acid-2-methylpiperazine salt was added at 130° C. and reacted for 3 h to obtain a mixed solution of n-butyl cyanoacrylate monomer;

[0039] Subsequently, the mixed solution was deacidified under vacuum to obtain crude n-butyl cyanoacrylate, and the crude product was placed in a distillation tower for distillation at a distillation temperature of 80° C. and a reflux ratio of 4:1 to obtain 185.34 g of pure n-butyl cyanoacrylate;

[0040] (3) 375.03 g of the above methylene diacetate and 400 g of octyl cyanoacetate were added to a three-necked flask, and 4.5 g of p-toluenesulfonic acid-2-methylpiperazine salt was added at 150° C., and the mixture was reacted for 6 h to obtain a octyl cyanoacrylate mixed solution;

[0041] The mixed solution was then deacidified under vacuum to obtain a crude product of 2-octyl cyanoacrylate, and the crude product was then placed in a distillation tower for distillation at a distillation temperature of 100° C. The reflux ratio was controlled at 5:1 to obtain 392.14 g of pure 2-octyl cyanoacrylate;

[0042] (4) Weigh 10 g of SiO2-MPS (γ-methacryloxypropyltrimethoxysilane) composite particles, 0.5 g of azobisisobutyronitrile (AIBN), 50 g of methyl methacrylate (MMA) and 200 g of anhydrous ethanol in a three-necked flask, react and stir at 85°C for 6 h to obtain a SiO2-MPS-PMMA mixed solution, then filter the mixed solution under reduced pressure to remove the solvent and wash it with distilled water, dry and grind it at 50°C, and pass it through an 80-mesh sieve to obtain a SiO2-MPS-PMMA solid powder;

[0043] The SiO2-MPS-PMMA solid powder was extracted with 100 mL of hot acetone in a Soxhlet extractor for 48 h, and the residual product was dried to obtain a PMMA modifier;

[0044] (5) Add 100 g of the above-prepared n-butyl cyanoacrylate and sec-octyl cyanoacrylate, 1 g of sulfur dioxide, 5 mg of hydroquinone, and 0.06 g of butyl hydroxyanisole into a three-necked flask and stir at room temperature for 30 min;

[0045] Then, 5 g of the PMMA modifier prepared above was slowly added, and the temperature was raised to 75° C. and stirred for 2 h until the solid powder was completely dissolved, thereby obtaining a vein closure adhesive.

[0046] Embodiment 2:

[0047] The present embodiment provides a venous closure adhesive and a preparation method thereof. The only difference between the present embodiment and the embodiment 1 is that the amounts of some substances involved in step (5) are different, specifically, 100 g of n-butyl cyanoacrylate, 0 g of sec-octyl cyanoacrylate, 2 mg of sulfur dioxide, 0.04 g of butyl hydroxyanisole and 10.1 g of PMMA modifier, and finally a venous closure adhesive is prepared.

[0048] Embodiment 3:

[0049] The present embodiment provides a venous closure adhesive and a preparation method thereof. The only difference between the present embodiment and the embodiment 1 is that the amounts of some substances involved in step (5) are different, specifically, 100 g of n-butyl cyanoacrylate, 25 g of sec-octyl cyanoacrylate, 2.5 mg of sulfur dioxide, 6.25 mg of hydroquinone, 0.05 g of butyl hydroxyanisole and 12.6 g of PMMA modifier, and finally a venous closure adhesive is prepared.

[0050] Embodiment 4:

[0051] The present embodiment provides a venous closure adhesive and a preparation method thereof. The only difference between the present embodiment and the embodiment 1 is that the amounts of some substances involved in step (5) are different, specifically, 75 g of n-butyl cyanoacrylate, 25 g of sec-octyl cyanoacrylate, 2 mg of sulfur dioxide, 0.04 g of butyl hydroxyanisole and 10.1 g of PMMA modifier, and finally a venous closure adhesive is prepared.

[0052] Embodiment 5:

[0053] The present embodiment provides a venous closure adhesive and a preparation method thereof. The only difference between the present embodiment and the embodiment 1 is that the amounts of some substances involved in step (5) are different, specifically, 50 g of n-butyl cyanoacrylate, 25 g of sec-octyl cyanoacrylate, 1.5 mg of sulfur dioxide, 3.75 mg of hydroquinone, 0.03 g of butyl hydroxyanisole and 7.6 g of PMMA modifier, and finally a venous closure adhesive is prepared.

[0054] Embodiment 6:

[0055] The present embodiment provides a venous closure adhesive and a preparation method thereof. The only difference between the present embodiment and the embodiment 1 is that the amounts of some substances involved in step (5) are different, specifically, 80 g of n-butyl cyanoacrylate, 20 g of sec-octyl cyanoacrylate, 2 mg of sulfur dioxide, 0.04 g of butyl hydroxyanisole and 17.6 g of PMMA modifier, and finally a venous closure adhesive is prepared.

[0056] Embodiment 7:

[0057] The present embodiment provides a venous closure adhesive and a preparation method thereof. The only difference between the present embodiment and the embodiment 1 is that the amounts of some substances involved in step (5) are different, specifically, 80 g of n-butyl cyanoacrylate, 20 g of sec-octyl cyanoacrylate, 2 mg of sulfur dioxide, 0.04 g of butyl hydroxyanisole and 22 g of PMMA modifier, and finally a venous closure adhesive is prepared.

[0058] Embodiment 8:

[0059] The present embodiment provides a venous closure adhesive and a preparation method thereof. The only difference between the present embodiment and the embodiment 1 is that the amounts of some substances involved in step (5) are different, specifically, 80 g of n-butyl cyanoacrylate, 20 g of sec-octyl cyanoacrylate, 2 mg of sulfur dioxide, 0.04 g of butyl hydroxyanisole and 25 g of PMMA modifier, and finally a venous closure adhesive is prepared.

[0060] Comparative Example 1

[0061] This embodiment provides a vein closure adhesive, which is a commercially available medical adhesive, specifically, 100 g of n-butyl cyanoacrylate, 0 g of sec-octyl cyanoacrylate, 2 mg of sulfur dioxide, 5 mg of hydroquinone, 0.04 g of butyl hydroxyanisole and 0 g of PMMA modifier.

[0062] In the present invention, the performance of the vein closure adhesive prepared in the above embodiments and comparative examples is tested and characterized. The specific test methods of the above performances are as follows:

[0063] (1) Curing time test

[0064] At ambient temperature, add 50 mL of 0.3 g / L sodium bicarbonate solution to a 90 mm diameter dish, use a 1 ml Pasteur pipette to draw up the product, drop a drop about 5 mm above the liquid surface, start timing, wait for the adhesive to solidify, and record the adhesive solidification time.

[0065] (2) Viscosity test

[0066] 2 ml of the product was taken with a pipette and placed in the sample cell of the Brookfield viscometer. The viscosity of the product was tested using a CPA-41Z rotor at (25±1°C) and a rotation speed of 60 rpm.

[0067] (3) Formaldehyde residue test

[0068] ① Measure 5 ml of water, add 5 ml of acetylacetone, shake well, place in a 40°C water bath for 40 minutes, then take out and measure the absorbance at a wavelength of 412 nm according to the UV-Vis spectrophotometry method (General Chapter 0401, Part 4, 2020 edition of the Chinese Pharmacopoeia), which is the blank control.

[0069] ② Take 100μg / ml standard formaldehyde solution and dilute it into 0.5pg / ml, 1pg / ml, 5μg / ml, 25pg / ml, 50μg / ml, and 75μg / ml standard solutions respectively. Accurately weigh 1ml of each of the above standard products, add water to 5ml, add 5ml of acetylacetone color developing solution, shake well, place in a 40℃ water bath for 40 minutes, then take out and cool to room temperature. According to the general rule 0401 UV-visible spectrophotometry in Part 4 of the 2020 edition of the "Chinese Pharmacopoeia", the absorbance was measured at a wavelength of 412nm.

[0070] ③ Weigh about 0.3g of skin adhesive and evenly spread it on a sterilized R2A agar solid culture medium with a diameter of 90mm. Leave it for 1 hour. After it is completely solidified, peel off the film, accurately weigh its mass m1, cut it into pieces, and extract it at a ratio of 0.1g / ml at (37±1)℃ for 8h. Take 1ml of the extract, add water to 5ml, add 5ml of acetylacetone color developing solution, shake well, place it in a 40℃ water bath for 40 minutes, then take it out and cool it to room temperature. According to the general rule 0401 UV-visible spectrophotometry in Part 4 of the 2020 edition of the "Chinese Pharmacopoeia", the absorbance was measured at a wavelength of 412nm.

[0071] Perform a linear regression on the absorbance of the standard solution using the formaldehyde concentration to obtain the linear regression equation; substitute the absorbance of the test sample into the linear regression equation to obtain the free formaldehyde content of the test sample.

[0072] (4) T-peel strength test

[0073] Apply the product to the designated position of the test product and test it according to the method in Part 2: T-peel tensile bearing strength of "YY / T 0729.2-2009 Test Method for Bonding Performance of Medical Adhesives".

[0074] (5) Wound closure strength test

[0075] Place the designated position of the test article and test it according to the method in Part 4: Wound Closure Strength of "YY / T 0729.4-2009 Test Method for Adhesive Properties of Medical Adhesives".

[0076] (6) Adhesive compliance test

[0077] At an ambient temperature of (23±2)℃, add 50ml of 0.3g / L sodium bicarbonate solution to a 90mm diameter dish, use a 1ml Pasteur pipette to draw the product, and drop a drop about 5mm above the liquid surface. After solidification into a film, lift the film up 5 times continuously without breaking.

[0078] (7) Adhesive operability

[0079] Use a Luer lock syringe to draw up the product, connect a 910mm long delivery catheter to the syringe head, push the syringe with an injection gun, and observe whether the adhesive flows smoothly out of the catheter.

[0080] The specific test results are listed in the following table:

[0081] Table 1 Performance test data table of Examples 1-8 and Comparative Example 1

[0082]

[0083] Through the above performance test, it can be seen from the data in the comparison table that the cyanoacrylate ratio in Examples 3-5 changes, and the curing time, T-peel strength and wound closure strength of the product have certain changing rules. With the reduction of the cyanoacrylate ratio, the curing time, T-peel strength and wound closure strength all show a downward trend, and the viscosity shows a gradual upward trend. This is because the content of octyl cyanoacrylate increases, the molecular weight of octyl cyanoacrylate is large, and the longer molecular chain increases the difficulty of intermolecular polymerization. The macroscopic manifestation is that the curing time is extended, the strength decreases, and the viscosity increases. In terms of curing time and viscosity, the curing time of the reference substance is too short, the viscosity is low, and the doctor does not have time to operate the operation, which can easily cause ectopic embolism of the vein.

[0084] From Examples 6-8, it can be seen that as the content of the modified thickener increases, the viscosity of the adhesive gradually increases. When the content of the modified thickener is too much (Example 8), the adhesive is thicker, the compliance after curing becomes worse, the operability is poor, and it is not conducive to the doctor's surgical operation. It can be seen that adding PMMA modified powder can improve the compliance of the adhesive, and the addition range is 8%-17%.

[0085] It is noteworthy that no formaldehyde residue was detected in Examples 3-8, while the control showed a higher formaldehyde residue, which confirmed the feasibility of the process route of the present invention and solved the problem of limited application of cyanoacrylate formaldehyde residue in human body.

[0086] At the same time, in the present invention, according to the requirements of GB / T 16886.5 "Biological Evaluation of Medical Devices" Part 5: In vitro Cytotoxicity Test for Cytotoxicity Test, L-929 was selected as the test cell line, and the commercially available medical adhesives in Example 6 and Comparative Example 1 were filmed and then the samples were formed, and the sample mass was about 0.3 g. After the samples were sterilized, they were placed in the culture medium to prepare the sample extracts, and 4 extract samples (100% extract, 75% extract, 50% extract, 25% extract) were prepared for each group, blank control samples, negative control samples, and positive control samples. The sample culture medium extract was used for L929 cell culture, and cultured for 72 hours at 37°C and 5% CO2, and then the cell survival rate was detected by MTT method (as shown in Table 2 below), and the results of each group were averaged. The growth conditions of the extracts of the adhesive in Example 6 and the commercially available medical adhesive in each concentration group and the control group are shown in Table 3:

[0087] Table 2 Statistical analysis of cell survival rate data

[0088]

[0089] Table 3 Concentration composition of the extracts of the adhesive prepared in Example 6 and the commercially available medical adhesive and the growth of the control group

[0090]

[0091]

[0092] According to the cell survival rate data analysis in Table 3, there was no cell lysis and no decrease in cell proliferation in the 100% concentration group of the product extract after adding PMMA powder in Example 6. It was judged that the cytotoxicity morphology of the test sample extract 100% concentration group was grade 0, and there was no cytotoxic reaction. Each extract showed good cell compatibility and could significantly promote cell growth, and the cell survival rate was above 90%. However, in the 100% concentration group of the commercial medical adhesive extract, a large number of cells died, and the reason was that the commercial adhesive contained a large amount of formaldehyde that caused cell death, indicating that the commercial medical adhesive had a large cytotoxicity.

[0093] In addition, according to the requirements of Part 10: Irritation and Skin Sensitization Test of GB / T 16886.10-2017 "Biological Evaluation of Medical Devices", New Zealand white rabbits were selected as a suitable animal model for evaluating intradermal reactions. Before the test, a sufficient area of ​​hair on both sides of the animal's back spine was removed to prepare for the injection of the extract.

[0094] The extract of the sample of Example 6 was selected to intradermally inject 0.2 mL of the extract prepared with a polar (or non-polar) solvent into five points on one side of the spine of each rabbit, and a polar (or non-polar) solvent control solution was injected into the other side of the spine of each rabbit. The sample was prepared according to the ratio (sample: extract volume) in Table 4, and the control solution was prepared under the same conditions. The condition of each injection point was observed and recorded, and the tissue reaction scores of erythema and edema at each site at (24±2)h, (48±2)h and (72±2)h were scored, and the test results were recorded in Tables 5 and 6.

[0095] Table 4 Sample intradermal test preparation table

[0096]

[0097] Table 5 Intradermal irritation reaction scoring results (polar extraction group)

[0098]

[0099]

[0100] Table 6 Intradermal irritation reaction scoring results (non-polar extraction group)

[0101]

[0102] Table 7 New Zealand rabbit intradermal test results

[0103]

[0104] Comparison and analysis of the intradermal irritation experimental data show that: each injection point was scored as zero, and the adhesive with the addition of polymethyl methacrylate thickener did not cause intradermal reaction in New Zealand rabbits, which shows that the prepared adhesive has good compatibility and safety in use, further confirming the feasibility of the present invention.

[0105] Finally, the present invention also selects healthy rabbits (weighing 2-3 kg), selects a suitable puncture point, cleans the puncture site (marginal auricular vein) with a disinfectant, inserts a puncture needle from above, inserts the needle into the vein, cleans the blood in the vein with saline, replaces the syringe containing the adhesive (the adhesive prepared in Example 6), injects the adhesive into the marginal auricular vein of the rabbit through the syringe, presses for 3 minutes, and observes the closure of the rabbit vein.

[0106] From the effect after blood vessel closure, it can be seen that the adhesive sealed area is white, and no blood flows through the sealed area after the blood vessel is closed, indicating that the rabbit's veins are completely closed by the adhesive, thereby confirming that the prepared adhesive has a good effect in treating varicose veins.

[0107] In summary, the present invention has developed a process for preparing cyanoacrylate adhesive without formaldehyde, breaking through the barrier that cyanoacrylate adhesive must be synthesized with formaldehyde. The product does not contain formaldehyde, solving the problem of limited in vivo application of "formaldehyde-containing adhesive". It provides patients with a new varicose vein treatment solution, solving the problem of large trauma of traditional technology, long repair cycle and high recurrence rate of existing thermal ablation and hardening agent technology, and achieving the effect of permanent closure of blood vessels.

[0108] The PMMA modifier proposed in the present invention is a new approach for adjusting the viscosity of a cyanoacrylate adhesive system. Compared with pure PMMA materials, the modified PMMA can not only achieve controllable viscosity of the adhesive, but also has good biocompatibility and ultra-high bonding performance, thus solving the problem of ectopic embolism during curing due to low viscosity.

[0109] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the contents of the present invention and implement them accordingly. They cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A vein closure adhesive, made by reacting raw materials, characterized in that: The raw materials include: cyanoacrylate monomer, PMMA modifier, inhibitor, stabilizer and antioxidant; Wherein, the feed mass ratio of the PMMA modifier is 5%-25% of the cyanoacrylate monomer; The mass ratio of the polymerization inhibitor is 0.002%-0.01% of the cyanoacrylate monomer; The feed mass ratio of the stabilizer is 0.005%-0.1% of the cyanoacrylate monomer; The feeding mass ratio of the antioxidant is 0.02%-0.06% of the cyanoacrylate monomer.

2. A vein sealing adhesive according to claim 1, characterized in that: The cyanoacrylate monomer is prepared by reacting active methylene ester and cyanoacetate under the action of an organic salt catalyst, and the molar ratio of the active methylene ester, the cyanoacetate and the organic salt catalyst is (1.2-1.5):(0.9-1.1):(0.005-0.01).

3. A vein sealing adhesive according to claim 2, characterized in that: The cyanoacetate is a mixture of one or more selected from methyl cyanoacetate, ethyl cyanoacetate, n-butyl cyanoacetate, isobutyl cyanoacetate, n-pentyl cyanoacetate, n-octyl cyanoacetate, isooctyl cyanoacetate and sec-octyl cyanoacetate.

4. A vein sealing adhesive according to claim 2, characterized in that: The active methylene ester is prepared by reacting halogenated alkane / active methylene substances and acid anhydride under the action of quaternary ammonium salt catalyst, and the molar ratio of the halogenated alkane / active methylene substances, the acid anhydride and the quaternary ammonium salt catalyst is 0.5-1:1:0.005-0.

01.

5. A vein sealing adhesive according to claim 4, characterized in that: The halogenated alkane is a mixture of one or more selected from dichloromethane, dibromomethane and diiodomethane; The active methylene substances are polyaldehyde substances or polyketone substances; The acid anhydride substance is a mixture of one or more selected from formic anhydride, acetic anhydride, caproic anhydride, ethylpropionic anhydride and maleic anhydride.

6. The vein sealing adhesive according to claim 1, characterized in that: The PMMA modifier is prepared by reacting modified SiO2 and acrylate substances under the action of an initiator.

7. The vein sealing adhesive according to claim 6, characterized in that: The modified SiO2 is a mixture of one or more selected from SiO2-γ-methacryloxypropyltrimethoxysilane, SiO2-methylpropylmethacryloxypropyltrimethoxysilane, SiO2-vinyltriethoxysilane and SiO2-vinyltri(β-methoxyethoxy)silane; The acrylic acid ester substance is a mixture of one or more selected from methyl methacrylate, ethyl methacrylate, ethyl acrylate and hydroxyethyl methacrylate.

8. The vein sealing adhesive according to claim 1, characterized in that: The polymerization inhibitor is a mixture of one or more selected from sulfuric acid, methane sulfonic acid, p-toluene sulfonic acid, dodecylbenzene sulfonic acid and sulfur dioxide; The stabilizer is a mixture of one or more selected from phenol, hydroquinone, thiobisphenol and catechol; The antioxidant is a mixture of one or more selected from butylated hydroxyanisole, p-propenylanisole and hydroxyanisole.

9. A method for preparing a vein closing adhesive according to any one of claims 1 to 8, characterized in that: The steps include: (1) Mixing halogenated alkane or active methylene substances with acid anhydrides and quaternary ammonium salt catalysts and heating at 65 to 85° C. for 3.5 to 4.5 hours to prepare active methylene esters; (2) mixing the active methylene ester with cyanoacetate and an organic salt catalyst at 120 to 160° C. and heating for 3 to 7 hours to obtain a cyanoacrylate monomer; (3) mixing the modified SiO2 with an acrylate substance and an initiator for reaction, and then post-treating to obtain a PMMA modifier; (4) The cyanoacrylate monomer is uniformly mixed with an inhibitor, a stabilizer, an antioxidant and the PMMA modifier to prepare the vein closure adhesive.

10. Use of the vein-sealing adhesive according to any one of claims 1 to 8 in treating varicose veins.

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