Alpha-isooctyl cyanoacrylate adhesive and preparation method thereof

Abstract

The invention relates to the technical field of adhesive preparation, in particular to an alpha-isooctyl cyanoacrylate adhesive and a preparation method thereof. The alpha-isooctyl cyanoacrylate adhesive is prepared from the following raw materials in parts by weight: 90.0 to 99.0 parts of base glue, 0.05 to 0.2 part of a polymerization inhibitor, 0.1 to 1.0 part of a stabilizer, 0.5 to 2 parts of a thickening agent and 0.1 to 0.5 part of an antibacterial agent, the base rubber at least comprises alpha-cyanoacrylate isooctyl ester; the polymerization inhibitor is at least one of hydroquinone, trifluoroacetic acid and glacial acetic acid; the stabilizer is sulfur dioxide and / or p-toluenesulfonic acid; the antibacterial agent is an inorganic mineral loaded with overplated metal single atoms. The alpha-isooctyl cyanoacrylate adhesive provided by the invention can be used for quickly suturing wounds and also has the effects of resisting bacteria, diminishing inflammation and accelerating wound healing.

Description

Technical Field

[0001] The present application relates to the technical field of adhesive preparation, and in particular to an α-isooctyl cyanoacrylate adhesive and a preparation method thereof. Background Art

[0002] α-isooctyl cyanoacrylate adhesive, as a medical adhesive, has changed the traditional medical method of relying solely on needle and thread to suture wounds. Replacing needle and thread suture with α-isooctyl cyanoacrylate adhesive has the following advantages: wound suturing is simple and less likely to cause secondary damage to the wound. It can also be used as an auxiliary in soft tissues, internal organs, bones and other parts that are difficult to suture with needle and thread, thus expanding its scope of application.

[0003] The wound closure mechanism of α-isooctyl cyanoacrylate adhesive: The α-isooctyl cyanoacrylate contained in α-isooctyl cyanoacrylate adhesive has a very low double bond electron cloud density due to the cyano and ester groups attached to the α carbon atom in its structure, resulting in strong electron absorption. In the presence of extremely small amounts of anionic media, anion-mediated intermolecular polymerization can occur instantly, achieving rapid wound closure. Extremely small amounts of anionic media, such as amino-NH2 and hydroxyl-OH groups on the surface of biological tissue, and trace amounts of weakly basic substances such as water vapor, ensure that α-isooctyl cyanoacrylate adhesive can quickly close wounds.

[0004] At present, although the existing α-cyanoacrylate medical adhesives can achieve good wound suture effects, they do not have bactericidal and disinfecting effects. In actual use, due to their slow degradation, they may cause new inflammation at the sutured wound site and even hinder further wound healing, limiting their practical value. Summary of the Invention

[0005] In order to solve the problem that α-cyanoacrylate medical adhesives in the prior art have poor sterilization and disinfection efficacy, and in actual use, due to their slow degradation, they may cause new inflammation at the sutured wound site and even hinder further wound healing. The present invention provides an α-cyanoacrylate isooctyl ester adhesive and a preparation method thereof.

[0006] The present invention provides an α-isooctyl cyanoacrylate adhesive, which is achieved through the following technical solutions:

[0007] An α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.0-99.0 parts of a base glue, 0.05-0.2 parts of a polymerization inhibitor, 0.1-1.0 parts of a stabilizer, 0.5-2 parts of a thickener, and 0.1-0.5 parts of an antibacterial agent; the base glue at least includes α-isooctyl cyanoacrylate; the polymerization inhibitor is at least one of hydroquinone, trifluoroacetic acid, and glacial acetic acid; the stabilizer is sulfur dioxide and / or p-toluenesulfonic acid; and the antibacterial agent is an inorganic mineral loaded with over-plated metal atoms.

[0008] The present invention adopts an inorganic mineral loaded with plated metal single atoms as an antibacterial agent, which gives the cyanoacrylate isooctyl ester adhesive a rapid wound suturing effect, and also gives it good antibacterial and anti-inflammatory effects, which can promote blood coagulation, accelerate wound healing, and enhance the use value of the cyanoacrylate isooctyl ester adhesive.

[0009] Preferably, the polymerization inhibitor is hydroquinone.

[0010] Preferably, the stabilizer is p-toluenesulfonic acid.

[0011] Preferably, the base glue is isooctyl α-cyanoacrylate.

[0012] Preferably, the inorganic mineral loaded with overplated metal single atoms includes an inorganic mineral carrier and an overplated metal element loaded on the inorganic mineral carrier in the form of a single atom, the inorganic mineral carrier is one of zeolite powder, montmorillonite, calcium carbonate, and shell powder; the overplated metal element is at least one of Ga, Fe, Zn, Cu, and Mg.

[0013] Preferably, the inorganic mineral carrier is zeolite powder, and the loading amount of the over-plated metal element is 0.5-5 wt%.

[0014] Preferably, the overplating metal elements are Ga, Fe, Zn, Cu, and Mg.

[0015] By adopting the above technical solution, the isooctyl cyanoacrylate adhesive is given good antibacterial and anti-inflammatory effects, which can promote blood coagulation, accelerate hemostasis and wound healing.

[0016] Preferably, the thickener is at least one of carboxymethyl cellulose, sodium hyaluronate, kamut gum, and chitosan.

[0017] Further preferably, the carboxymethyl cellulose is amino acid-modified carboxymethyl cellulose, which is prepared by reacting an amino acid with carboxymethyl cellulose, and the amino acid is at least one of aspartic acid, glycine, tyrosine, serine, threonine, and lysine.

[0018] The amino acid-modified carboxymethyl cellulose in the present invention can form a uniform dispersed phase in the adhesive, increase the viscosity of the α-isooctyl cyanoacrylate adhesive, enhance the fluidity of the adhesive, and improve the use effect of the α-isooctyl cyanoacrylate adhesive. In addition, the carboxymethyl cellulose is terminated with amino acids to reduce foreign body reactions, further eliminate inflammation caused by foreign body reactions, and improve the application range of the α-isooctyl cyanoacrylate adhesive.

[0019] Preferably, the α-isooctyl cyanoacrylate adhesive further comprises 5-10 parts of a toughening agent, wherein the toughening agent comprises at least four-arm polyethylene glycol, and the molecular weight of the four-arm polyethylene glycol is 2000-40000.

[0020] By adopting the above technical solution, the α-isooctyl cyanoacrylate adhesive can be toughened, and the degradation efficiency of the α-isooctyl cyanoacrylate adhesive can be improved. The inflammation problem caused by foreign body reaction can be further eliminated, and the application range of the α-isooctyl cyanoacrylate adhesive can be improved.

[0021] Preferably, the α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.3-90.5 parts of α-isooctyl cyanoacrylate, 8 parts of four-arm polyethylene glycol with a molecular weight of 2000-40000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.8 parts of amino acid modified carboxymethyl cellulose, and 0.2-0.4 parts of an antibacterial agent.

[0022] Preferably, the toughening agent is composed of four-arm polyethylene glycol and three-arm polyethylene glycol acrylate, the molecular weight of the three-arm polyethylene glycol acrylate is 2000-40000; the mass ratio of the four-arm polyethylene glycol to the three-arm polyethylene glycol acrylate is (3-4):1.

[0023] The introduction of four-arm polyethylene glycol and three-arm polyethylene glycol acrylate into the formula of α-isooctyl cyanoacrylate adhesive can improve the cross-linking density of α-isooctyl cyanoacrylate adhesive, thereby improving the overall mechanical strength and toughness of α-isooctyl cyanoacrylate adhesive, ensuring the quality of wound suture. At the same time, the degradation rate of α-isooctyl cyanoacrylate adhesive is adjusted, which can further eliminate the inflammation problem caused by foreign body reaction and improve the application range of α-isooctyl cyanoacrylate adhesive.

[0024] Preferably, the α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.3-90.5 parts of α-isooctyl cyanoacrylate, 2 parts of three-arm polyethylene glycol acrylate with a molecular weight of 2000-40000, 6 parts of four-arm polyethylene glycol with a molecular weight of 2000-40000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.8 parts of amino acid modified carboxymethyl cellulose, and 0.2-0.4 parts of an antibacterial agent.

[0025] The present invention provides a preparation method of isooctyl α-cyanoacrylate adhesive, which is achieved through the following technical scheme: A preparation method of isooctyl α-cyanoacrylate adhesive, comprising the following steps: first, exhausting air from a batching kettle with nitrogen; under nitrogen protection, adding accurately measured base glue, polymerization inhibitor, stabilizer, thickener, and antibacterial agent into the batching kettle; stirring and mixing at 80-120 rpm for 10-20 minutes; after the materials are evenly mixed, adjusting the kettle pressure to 0.04-0.06 MPa for defoaming treatment for 15-30 minutes; filling, sealing, and storing to obtain the isooctyl α-cyanoacrylate adhesive.

[0026] The preparation method of the present invention is relatively simple and is easy to implement in industrial batch production.

[0027] In summary, this application has the following advantages:

[0028] 1. The α-isooctyl cyanoacrylate adhesive provided in the present invention can quickly suture wounds while having antibacterial and anti-inflammatory effects and accelerating wound healing, solving the problem that existing α-cyanoacrylate medical adhesives have poor bactericidal and disinfecting efficacy and are prone to causing secondary damage.

[0029] 2. The toughening agent introduced in the present invention can, on the one hand, improve the crosslinking density of the isooctyl α-cyanoacrylate adhesive, enhance the overall mechanical strength and toughness of the isooctyl α-cyanoacrylate adhesive, and ensure the quality of wound suture. On the other hand, it can increase the degradation rate of the isooctyl α-cyanoacrylate adhesive, which is beneficial to eliminate the inflammation problem caused by foreign body reaction and improve the application range of the isooctyl α-cyanoacrylate adhesive.

[0030] 3. The preparation method of the present invention is relatively simple and is easy to implement in industrial batch production. DETAILED DESCRIPTION

[0031] In order to further understand the inventiveness and technical advancement of the present invention, the preferred embodiments of the present invention are discussed in detail below with reference to examples and comparative examples. It should be noted that this specific embodiment is merely an explanation of the technical solution of the present invention and is not intended to limit the present invention. After reading this specification, those skilled in the art may make modifications to this embodiment as needed without contributing to creativity, but as long as they are within the scope of the claims of the present invention, they are protected by patent law.

[0032] Example

[0033] An α-isooctyl cyanoacrylate adhesive is made from the following raw materials in parts by weight: 90.0-99.0 parts of a base adhesive, 0.05-0.2 parts of a polymerization inhibitor, 0.1-1.0 parts of a stabilizer, 0.5-2 parts of a thickener, and 0.1-0.5 parts of an antimicrobial agent. The antimicrobial agent, a core additive, is an inorganic mineral loaded with metal atoms that exhibits hemostatic, healing, and antibacterial and anti-inflammatory properties.

[0034] The inorganic mineral supporting the overplating metal single atoms comprises an inorganic mineral carrier and an overplating metal element supported on the inorganic mineral carrier in the form of single atoms. The inorganic mineral carrier is one of zeolite powder, montmorillonite, calcium carbonate, and shell powder. The inorganic mineral carrier is preferably zeolite powder. The overplating metal element is at least one of Ga, Fe, Zn, Cu, and Mg, and the loading amount of the overplating metal element is 0.5-5 wt%.

[0035] The base adhesive comprises at least isooctyl α-cyanoacrylate, and can be composed of isooctyl α-cyanoacrylate and at least one of n-butyl α-cyanoacrylate, ethyl α-cyanoacrylate, propyl α-cyanoacrylate, isoethyl α-cyanoacrylate, and n-octyl α-cyanoacrylate.

[0036] α-Isooctyl cyanoacrylate adhesive contains active double bonds, so it is necessary to select a suitable polymerization inhibitor, which is preferably at least one of hydroquinone, trifluoroacetic acid, and glacial acetic acid.

[0037] The stabilizer in the α-isooctyl cyanoacrylate adhesive can prevent the adhesive from delamination, gelling or deterioration during use and storage. The stabilizer is preferably sulfur dioxide and / or p-toluenesulfonic acid.

[0038] The thickener in the isooctyl α-cyanoacrylate adhesive forms a uniform dispersed phase within the adhesive, increasing its viscosity, improving its fluidity, and enhancing its performance. The thickener is at least one of carboxymethyl cellulose, sodium hyaluronate, kamm gum, and chitosan.

[0039] Preferably, the thickener is amino acid modified carboxymethyl cellulose. Amino acid modified carboxymethyl cellulose is end-capped with amino acids to reduce foreign body reactions, further eliminate inflammation problems caused by foreign body reactions, and improve the application range of α-isooctyl cyanoacrylate adhesives.

[0040] The amino acid modified carboxymethyl cellulose is prepared by the reaction of amino acid and carboxymethyl cellulose, wherein the amino acid is a hydrophilic amino acid, and the amino acid is at least one of aspartic acid, glycine, tyrosine, serine, threonine and lysine.

[0041] To improve the overall toughness of the 2-ethylhexyl α-cyanoacrylate adhesive, a toughening agent is added to the 2-ethylhexyl α-cyanoacrylate adhesive formula. The toughening agent is a four-arm polyethylene glycol with a molecular weight of 2,000-40,000, or a toughening agent composed of a four-arm polyethylene glycol with a molecular weight of 2,000-40,000 and a three-arm polyethylene glycol acrylate with a molecular weight of 2,000-40,000 in a mass ratio of (3-4):1.

[0042] When the toughening agent is four-arm polyethylene glycol with a molecular weight of 2000-40000, the formula of the α-isooctyl cyanoacrylate adhesive is as follows: 90.3-90.5 parts of α-isooctyl cyanoacrylate, 8 parts of four-arm polyethylene glycol with a molecular weight of 2000-40000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.8 parts of amino acid modified carboxymethyl cellulose, and 0.2-0.4 parts of antibacterial agent.

[0043] When the toughening agents are four-arm polyethylene glycol with a molecular weight of 2000-40000 and three-arm polyethylene glycol acrylate with a molecular weight of 2000-40000, the formula of the α-isooctyl cyanoacrylate adhesive is as follows: 90.3-90.5 parts of α-isooctyl cyanoacrylate, 2 parts of three-arm polyethylene glycol acrylate with a molecular weight of 2000-40000, 6 parts of four-arm polyethylene glycol with a molecular weight of 2000-40000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.8 parts of amino acid modified carboxymethyl cellulose, and 0.2-0.4 parts of antibacterial agent.

[0044] A preparation method of isooctyl α-cyanoacrylate adhesive comprises the following steps: exhausting air from a batching kettle with nitrogen; adding accurately measured base glue, polymerization inhibitor, stabilizer, thickener, and antibacterial agent into the batching kettle under nitrogen protection; stirring and mixing at 80-120 rpm for 10-20 minutes; after the materials are evenly mixed, adjusting the kettle pressure to 0.04-0.06 MPa for defoaming treatment for 15-30 minutes; filling, sealing, and storing to obtain the isooctyl α-cyanoacrylate adhesive.

[0045] Example 1: An α-isooctyl cyanoacrylate adhesive is made from the following raw materials in parts by weight: 98.5 parts of α-isooctyl cyanoacrylate, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.1 parts of an antibacterial agent.

[0046] The antimicrobial agent is an inorganic mineral loaded with overplated metal atoms.

[0047] The preparation method of the antibacterial agent is as follows: step 1, dry-milling 1250 mesh 4A zeolite powder with a planetary ball mill at 80 rpm for 30 minutes to obtain 4A zeolite fine powder; step 2, preparing a transition metal ligand solution: dissolving 1g of calcium chloride, 1g of magnesium chloride, 1g of ferric chloride, 1g of zinc chloride, and 1g of copper chloride in 500g of distilled water and stirring and mixing to obtain a transition metal ligand solution; step 3, adding the 4A zeolite fine powder to the transition metal ligand solution, and the 4A zeolite fine powder and the transition metal ligand solution of Ga, Fe, Zn, Cu The ratio of the total mass of Mg is 24:1. It is placed in ultrasonic dispersion at room temperature at 40kHz for 30 minutes and then stirred at 400r / min for 12 hours. It is volatilized at high temperature and the solvent is evaporated to obtain a solid. In step four, the obtained solid is fully ground in a ball mill at a speed of 50r / min for 10 minutes to obtain a solid powder. The obtained solid powder is heated to 500°C at 5°C / min in a tube furnace and kept warm for 2 hours. The furnace is opened and cooled to room temperature. The obtained solid material is placed in a planetary ball mill and dry-milled at 80rpm for 30 minutes to obtain the finished antibacterial agent.

[0048] A preparation method of an α-isooctyl cyanoacrylate adhesive comprises the following steps: firstly exhausting air from a batching kettle with nitrogen; then, under nitrogen protection, adding 98.5 parts of α-isooctyl cyanoacrylate, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.1 parts of an antibacterial agent into the batching kettle; stirring and mixing at 90 rpm for 15 minutes; after the materials are evenly mixed, adjusting the kettle pressure to 0.05 MPa and maintaining the pressure at 90 rpm for defoaming for 30 minutes; then, filling, sealing, and storing the product to obtain the α-isooctyl cyanoacrylate adhesive.

[0049] The difference between Example 2 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made from the following raw materials in parts by weight: 98.3 parts of α-isooctyl cyanoacrylate, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.3 parts of an antibacterial agent.

[0050] The difference between Example 3 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made from the following raw materials in parts by weight: 98.1 parts of α-isooctyl cyanoacrylate, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.5 parts of an antibacterial agent.

[0051] The difference between control group A and Example 1 is that the antibacterial agent is replaced by commercially available medical nano silver ions (provided by Hebei Mutun Mineral Products Co., Ltd., with a particle size of 6 nm).

[0052] Comparative Example 1 differs from Example 1 in that the α-cyanoacrylate adhesive is made from the following raw materials in parts by weight: 98.5 parts of α-cyanoacrylate, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.1 parts of 4A zeolite fine powder. The 4A zeolite fine powder was prepared by dry-milling 1250-mesh 4A zeolite powder at 80 rpm in a planetary ball mill for 30 minutes.

[0053] The difference between Comparative Example 2 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made from the following raw materials in parts by weight: 98.55 parts of α-isooctyl cyanoacrylate, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.05 parts of an antibacterial agent.

[0054] The difference between Comparative Example 3 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made from the following raw materials in parts by weight: 98.0 parts of α-isooctyl cyanoacrylate, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.6 parts of an antibacterial agent.

[0055] Performance test 1 - antibacterial experiment: The sample object is the film formed by the α-isooctyl cyanoacrylate adhesive in Examples 1-3 and Comparative Examples 1-3. The α-isooctyl cyanoacrylate adhesive is coated on a glass plate to form a film with a thickness of 100 μm ± 10 μm. The film is subjected to antibacterial tests against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans as bacterial species. The antibacterial test steps are as follows: Step 1, prepare fresh bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans) cultured for 18h-24h, wash the bacterial moss with 5mL PBS solution (0.03mol / L) to prepare a bacterial suspension, and dilute it with PBS to the required concentration (drop 100μL on the control sample and recover 1×10 4 -9×10 4cfu / plate), step 2, weigh a certain amount of test sample, disperse it in PBS to prepare a sample solution (concentration of 2000ppm), and place it in a 250ml conical flask; step 3, fix the conical flask on an oscillating shaker and shake it at 300r / min for 1 hour; step 4, at time 0 and after 1 hour of shaking, take 0.5mL of sample solution, or the sample solution appropriately diluted with PBS, inoculate the plate by the agar pour method, and incubate in a constant temperature box at 36-37 degrees for 18-24 hours for colony counting. The test is repeated 3 times, and the antibacterial rate is calculated according to the formula: X = (AB) / A × 100%, where: X - antibacterial rate, %; A - average colony count of the test sample before shaking; B - average colony count of the test sample after shaking.

[0056] Table 1: Antibacterial test parameters of α-isooctyl cyanoacrylate adhesives in Examples 1-3, Control Group A, and Comparative Examples 1-3

[0057]

[0058] Combining Examples 1-3 and Control Group A and Table 1, it can be seen that the antibacterial agent of the present invention can achieve good antibacterial and anti-inflammatory effects. Compared with the existing medical nanosilver ions at the same addition amount, the inorganic mineral loaded with over-plated metal atoms used in the present invention can achieve good antibacterial and anti-inflammatory effects.

[0059] Combining Examples 1-3 and Comparative Examples 1-3 and Table 1, it can be seen that the amount of antibacterial agent added in the present invention is controlled to be ≥0.1 parts. Too low an amount will affect the antibacterial effect, while too high an amount will affect the hardness of the medical glue. If the hardness of the medical glue is too high, the use scenario and healing effect of the medical glue will be required. Therefore, the amount of antibacterial agent added in the present invention is limited to 0.2-0.3 parts.

[0060] Performance test 2: Determination of the bonding strength of medical adhesive: At room temperature, take two pieces of pig skin (length 4cm, width 2cm, thickness 1cm), use a dropper to drop two drops of α-isooctyl cyanoacrylate adhesive (0.05mL*2) on the side surface of one pig skin, quickly overlap the side of the other pig skin, and test the bonding strength between the pig skins by pulling the pig skins in both directions.

[0061] Performance test 3: Determination of curing time of medical glue: After a certain period of overlap, the liquid glue between the pig skins is completely cured. The bonding strength curve determines the time point after the bonding is stable, which is recorded as the curing time.

[0062] Table 2: Adhesion test parameters of α-isooctyl cyanoacrylate adhesive in Examples 1-3, Control Group A, and Comparative Examples 1-3

[0063]

[0064] Combining Examples 1-3 and Control Group A, Comparative Examples 1-3 and Table 1, it can be seen that the addition of the antibacterial agent in the present invention has a relatively small effect on the curing time and bonding strength of the medical adhesive, that is, the inorganic mineral loaded with plated metal atoms as an antibacterial component can be adapted to the α-isooctyl cyanoacrylate adhesive formulation.

[0065] The degradation rate of the film formed by the α-isooctyl cyanoacrylate adhesive was studied based on the formula of α-isooctyl cyanoacrylate adhesive with an antibacterial agent addition of 0.3 parts.

[0066] The difference between Example 4 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.3 parts of α-isooctyl cyanoacrylate, 8 parts of four-arm polyethylene glycol with a molecular weight of 5000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.3 parts of an antibacterial agent.

[0067] The difference between Example 5 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.3 parts of α-isooctyl cyanoacrylate, 8 parts of four-arm polyethylene glycol with a molecular weight of 10,000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.3 parts of an antibacterial agent.

[0068] The difference between Example 6 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.3 parts of α-isooctyl cyanoacrylate, 8 parts of four-arm polyethylene glycol with a molecular weight of 20,000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.3 parts of an antibacterial agent.

[0069] The difference between Example 7 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.3 parts of α-isooctyl cyanoacrylate, 6 parts of four-arm polyethylene glycol with a molecular weight of 10,000, 2 parts of three-arm polyethylene glycol acrylate with a molecular weight of 5,000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.3 parts of an antibacterial agent.

[0070] The difference between Example 8 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.3 parts of α-isooctyl cyanoacrylate, 6 parts of four-arm polyethylene glycol with a molecular weight of 10,000, 2 parts of three-arm polyethylene glycol acrylate with a molecular weight of 10,000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.3 parts of an antibacterial agent.

[0071] The difference between Example 9 and Example 1 is that the α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.3 parts of α-isooctyl cyanoacrylate, 6 parts of four-arm polyethylene glycol with a molecular weight of 10,000, 2 parts of three-arm polyethylene glycol acrylate with a molecular weight of 20,000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of amino acid-modified carboxymethyl cellulose, and 0.3 parts of an antibacterial agent.

[0072] The difference between Example 10 and Example 9 is that the α-isooctyl cyanoacrylate adhesive is made of the following raw materials in parts by weight: 90.3 parts of α-isooctyl cyanoacrylate, 6 parts of four-arm polyethylene glycol with a molecular weight of 10,000, 2 parts of three-arm polyethylene glycol acrylate with a molecular weight of 20,000, 0.1 parts of hydroquinone, 0.4 parts of p-toluenesulfonic acid, 0.9 parts of carboxymethyl cellulose, and 0.3 parts of an antibacterial agent.

[0073] Performance test 4: Degradation performance of medical adhesive. 0.1 g of each of the α-isooctyl cyanoacrylate adhesives in Examples 2 and 4-10 were dropped onto a 2.5 × 3 cm glass slide. After they were completely cured, they were vacuum dried and their initial weights were weighed. The glass slides were placed in a 0.1 M phosphate buffer solution (PBS buffer solution, with a K2HPO4·3H2O concentration of 1.85 g / L and KH 2 The colloid was degraded in an Erlenmeyer flask containing 0.24 g / L PO₄, 8.0 g / L NaCl, and 0.20 g / L KCl. The flask was placed in a 37.5°C incubator for 14 days. After 14 days, the remaining solids were weighed and the degradation rate was calculated. This was used to assess the degradation performance. The lower the remaining solids, the greater the degradation, indicating a stronger degradation ability. Three replicates were tested, and the data were averaged. Degradation rate = (initial solid weight - residual solid weight) / initial solid weight. Control B was pure 2-ethylhexyl α-cyanoacrylate.

[0074] Table 3: Degradation performance test parameters of α-isooctyl cyanoacrylate adhesive in Example 2, Examples 4-10, and Control Groups AB

[0075] Group Degradation rate% Group Degradation rate% Control group A 4.05 Control group B 3.79 Example 2 4.12 Example 7 17.49 Example 4 19.15 Example 8 19.15 Example 5 21.03 Example 9 19.72 Example 6 21.63 Example 10 18.58

[0076] From Example 2, Examples 4-10, Control Groups AB and Table 3, it can be seen that using four-arm polyethylene glycol, or four-arm polyethylene glycol and three-arm polyethylene glycol acrylate as a toughening agent can improve the degradation performance of α-isooctyl cyanoacrylate adhesive, which is beneficial to eliminating the inflammation problem caused by foreign body reaction and improving the application range of α-isooctyl cyanoacrylate adhesive.

[0077] Performance test 5: In vitro cytotoxicity test is determined in accordance with GB / T16886.5-2017.

[0078] Performance test 6: Delayed-type hypersensitivity reaction test is determined in accordance with GB / T16886.10-2017.

[0079] Table 4: Allergy resistance test parameters of α-isooctyl cyanoacrylate adhesives in Examples 1-10, Control Groups AB and Comparative Examples 1-3

[0080] In vitro cytotoxicity assay Delayed-type hypersensitivity test Example 1 Level 0 Non-allergenic Example 2 Level 0 Non-allergenic Example 3 Level 0 Non-allergenic Example 4 Level 0 Non-allergenic Example 5 Level 0 Non-allergenic Example 6 Level 0 Non-allergenic Example 7 Level 0 Non-allergenic Example 8 Level 0 Non-allergenic Example 9 Level 0 Non-allergenic Example 10 Level 0 Non-allergenic Control group A Level 0 Localized erythema Control group B Level 0 Localized erythema Comparative Example 1 Level 0 Localized erythema Comparative Example 2 Level 0 Non-allergenic Comparative Example 3 Level 0 Non-allergenic

[0081] Combining Examples 1-10, Control Groups AB and Comparative Examples 1-3 and Table 4, it can be seen that the α-isooctyl cyanoacrylate adhesive of the present invention has low toxicity and good anti-allergic properties.

[0082] Performance Test 7: Guinea Pig Skin Incisional Adhesion Test: Fifteen adult guinea pigs (SPE guinea pigs from Kangda Biotechnology Co., Ltd.) were subjected to back hair removal and intraperitoneal injection of 45 mg / kg of sodium pentobarbital anesthetic. After disinfection of the back, a 2 cm long longitudinal incision was made approximately 1 cm from the midline of the back, reaching the muscular layer. After hemostasis, the skin incision was tightly closed. The α-isooctyl cyanoacrylate adhesives from Examples 2, 9, and Control A were quickly and evenly applied to the wound skin surface. The curing time was 30 seconds. Wound healing was observed every 24 hours.

[0083]

[0084]

[0085] Combining Example 2, Example 9, Control Group A and Table 5, it can be seen that the α-isooctyl cyanoacrylate adhesive of the present invention completed wound healing after 5 days in the guinea pig skin incision injury adhesion test, has relatively rapid wound healing performance, has no allergic reaction, and has good biocompatibility.

[0086] In summary, the α-isooctyl cyanoacrylate adhesive provided in the present invention can quickly suture wounds while having antibacterial and anti-inflammatory effects and accelerating wound healing.

Claims

1. An α-isooctyl cyanoacrylate adhesive, characterized in that: The invention is prepared from the following raw materials in parts by weight: 90.0-99.0 parts of base glue, 0.05-0.2 parts of polymerization inhibitor, 0.1-1.0 parts of stabilizer, 0.5-2 parts of thickener, and 0.1-0.5 parts of antibacterial agent; The base glue at least includes α-isooctyl cyanoacrylate; The polymerization inhibitor is at least one of hydroquinone, trifluoroacetic acid, and glacial acetic acid; The stabilizer is sulfur dioxide and or p-toluenesulfonic acid; The antibacterial agent is an inorganic mineral loaded with over-plated metal atoms.

2. The isooctyl α-cyanoacrylate adhesive according to claim 1, characterized in that: The inorganic mineral loaded with overplated metal single atoms includes an inorganic mineral carrier and an overplated metal element loaded on the inorganic mineral carrier in the form of a single atom, the inorganic mineral carrier is one of zeolite powder, montmorillonite, calcium carbonate, and shell powder; the overplated metal element is at least one of Ga, Fe, Zn, Cu, and Mg.

3. The isooctyl α-cyanoacrylate adhesive according to claim 2, characterized in that: The inorganic mineral carrier is zeolite powder, and the loading amount of the over-plated metal element is 0.5-5 wt %.

4. The isooctyl α-cyanoacrylate adhesive according to claim 1, characterized in that: The thickener is at least one of carboxymethyl cellulose, sodium hyaluronate, kamut gum and chitosan.

5. The isooctyl α-cyanoacrylate adhesive according to claim 4, characterized in that: The carboxymethyl cellulose is amino acid-modified carboxymethyl cellulose, which is prepared by reacting amino acids with carboxymethyl cellulose. The amino acid is at least one of aspartic acid, glycine, tyrosine, serine, threonine, and lysine.

6. The isooctyl α-cyanoacrylate adhesive according to claim 3, characterized in that: The invention also comprises 5-10 parts of a toughening agent, wherein the toughening agent at least comprises four-arm polyethylene glycol, and the molecular weight of the four-arm polyethylene glycol is 2000-40000.

7. The isooctyl α-cyanoacrylate adhesive according to claim 6, characterized in that: The invention is prepared from the following raw materials in parts by weight: 90.3-90.5 parts of isooctyl α-cyanoacrylate, 8 parts of four-arm polyethylene glycol with a molecular weight of 2000-40000, 0.1 part of hydroquinone, 0.4 part of p-toluenesulfonic acid, 0.8 part of amino acid modified carboxymethyl cellulose, and 0.2-0.4 part of an antibacterial agent.

8. The isooctyl α-cyanoacrylate adhesive according to claim 6, characterized in that: The toughening agent is composed of four-arm polyethylene glycol and three-arm polyethylene glycol acrylate, the molecular weight of the three-arm polyethylene glycol acrylate is 2000-40000; the mass ratio of the four-arm polyethylene glycol to the three-arm polyethylene glycol acrylate is (3-4):

1.

9. The isooctyl α-cyanoacrylate adhesive according to claim 6, characterized in that: The invention is prepared from the following raw materials in parts by weight: 90.3-90.5 parts of isooctyl α-cyanoacrylate, 2 parts of three-arm polyethylene glycol acrylate with a molecular weight of 2000-40000, 6 parts of four-arm polyethylene glycol with a molecular weight of 2000-40000, 0.1 part of hydroquinone, 0.4 part of p-toluenesulfonic acid, 0.8 part of amino acid-modified carboxymethyl cellulose, and 0.2-0.4 part of an antibacterial agent.

10. A method for preparing the isooctyl α-cyanoacrylate adhesive according to any one of claims 1 to 9, characterized in that: The following steps are involved: The batching kettle is first exhausted of air with nitrogen. Under nitrogen protection, the accurately measured base glue, polymerization inhibitor, stabilizer, thickener and antibacterial agent are added into the batching kettle, and stirred and mixed at 80-120 rpm for 10-20 minutes. After the materials are evenly mixed, the kettle pressure is adjusted to 0.04-0.06 MPa for defoaming treatment for 15-30 minutes, and then the materials are filled, sealed and stored to obtain α-isooctyl cyanoacrylate adhesive.

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