An absorbable fast hemostatic adhesive and its preparation method and application

Abstract

The present invention provides an absorbable and rapidly hemostatic adhesive, its preparation method and application. The raw materials for preparing the adhesive include component A and component B: Component A includes cycloalkenone acetal compounds and oxidants; Component B includes vinyl monomers, crosslinking agents, hemostatic agents and reducing agents. The adhesive is formed by in-situ curing through free radical ring-opening polymerization under the initiation of an oxidation-reduction free radical polymerization initiator in the human body environment. It has a rapid bond closure, a slightly exothermic reaction, and will not burn the human body. After the free radical ring-opening polymerization of the cycloalkenone acetal compound, the main chain contains an ester bond structure, which can be degraded in the physiological environment, and the degradation rate at 8 weeks is >20%. The mild reaction conditions are conducive to the loading of hemostatic agents and antibacterial agents. As these substances are gradually exposed and released, they further endow the adhesive with the activated hemostatic effect and avoid bacterial infection. The adhesive is prepared and used immediately, the use process is simple, the ideal operation time window is 1-5 minutes, and it has strong clinical operability.

Description

Technical Field

[0001] The present invention belongs to the technical field of adhesives, and particularly relates to an absorbable and rapidly hemostatic adhesive, a preparation method thereof, and an application thereof. Background Art

[0002] Massive bleeding of wounds has always been the main cause of death in patient surgeries and wars. Rapid and effective hemostasis can save patients' lives at critical moments, which is of great clinical significance. In recent years, in response to the need for rapid hemostasis, various hemostatic materials have emerged on the market, mainly including zeolite dressings, chitosan dressings, gelatin sponges, oxidized regenerated cellulose, etc. These materials have a high water absorption rate and can quickly adhere to the wound to form a hemostatic microenvironment. However, the above-mentioned hemostatic materials have disadvantages such as low bonding strength and slow speed. α-Cyanoacrylate-based adhesives have a fast curing speed and high bonding strength, which can solve the above problems. In the early 1960s, cyanoacrylate adhesives were very popular, but in application, their biological toxicity restricted the development of this type of adhesive. It was found that modified monomers such as isobutyl cyanoacrylate, n-butyl cyanoacrylate, and n-octyl cyanoacrylate can be used to reduce the biological toxicity of cyanoacrylate adhesives. This discovery promoted the further development of medical soft tissue adhesives. However, at present, α-cyanoacrylate adhesives have problems such as high hardness, poor toughness, repeated abrasion that can cause tissue damage, and can also cause a series of problems including premature detachment or rupture of the adhesive film, and even reactive inflammatory reactions. Most seriously, due to its non-absorbable property, its clinical application is restricted to a certain extent. In addition, with the emergence of "super bacteria" due to the abuse of antibiotics, suppurative infection or specific bacterial infection of bleeding wounds may lead to tetanus, septicemia, pyemia, and toxemia, and even septic shock, which are all non-negligible factors causing death. Therefore, the new hemostatic material should not only have a strong coagulation ability, but also have the ability of antibacterial and anti-infection, so as to reduce the death of patients caused by factors such as postoperative infection and wound suppuration.

[0003] Based on the above situation, it is urgent to develop a new generation of hemostatic materials, which need to have the following characteristics: fast closing speed of the bleeding orifice, fast hemostasis speed, good biocompatibility, and absorbable by the human body. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide an absorbable and rapidly hemostatic adhesive, a preparation method thereof, and an application thereof. The adhesive is formed by in-situ curing through free radical ring-opening polymerization under the initiation of an oxidation-reduction free radical polymerization initiator in the human body environment, with rapid bonding and closing, slightly exothermic reaction, and will not burn the human body.

[0005] The present invention provides an absorbable and rapidly hemostatic adhesive, and the preparation raw materials include the following component A and component B:

[0006] The component A includes cycloalkenone acetal compounds and an oxidant;

[0007] The component B includes vinyl monomers, a crosslinking agent, a hemostatic agent, and a reducing agent.

[0008] In the present invention, the molar ratio of the vinyl monomer to the cycloalkenone acetal compound is 0.01 to 100:1;

[0009] The molar ratio of the crosslinking agent to the cycloalkenone acetal compound is 0.001 to 0.2:1;

[0010] The molar ratio of the hemostatic agent to the cycloalkenone acetal compound is 1×10 -7 ~1×10 -4 :1.

[0011] In the present invention, the component B further includes an antibacterial agent;

[0012] The molar ratio of the antibacterial agent to the cycloalkenone acetal compound is 1×10 -5 ~1×10 -4 :1.

[0013] In the present invention, the cycloalkenone acetal compounds include one or more of 2-methylene-1,3-dioxepane, 2-methylene-4-phenyl-1,3-dioxolane, 5,6-benzo-2-methylene-1,3-dioxepane, and 4,7-dimethyl-2-methylene-1,3-dioxepane;

[0014] The vinyl monomers include one or more of (meth)acrylic acid, (meth)acrylate, vinyl acetate, maleimide polyethylene glycol carboxylic acid, biotin-PEG-6-maleimide, m-maleimide benzoic acid succinimide ester, 6-maleimide hexanoic acid, ethylene glycol vinyl ether, tetraethylene glycol mono vinyl ether, ethylene (2-chloroethyl) ether, 2-methacryloyloxyethyl phosphorylcholine, 10-(2-methacryloyloxy) phosphoric acid monodecyl ester, (meth)acryloyloxy sulfobetaine, 4-methacryloyloxyethyl trimellitic anhydride, methacryloyldopamine, N-acryloyl (trimethylol) aminomethane, polyethylene glycol methacrylate, N,N-dimethylaminoethyl methacrylate, (meth)allylamine, and O-allyl hydroxylamine.

[0015] In the present invention, the crosslinking agent is a monomer containing two vinyl units and / or a monomer containing more than two vinyl units;

[0016] The hemostatic agents include one or more of vitamin K1, vitamin K4, hemocoagulase, carbazochrome sodium sulfonate, aminocaproic acid, carbazochrome, and elot.

[0017] The antibacterial agent includes one or more of silver ions, zinc ions, antibacterial peptides, coumarin compounds, polyguanidine polymers, and benzalkonium chloride.

[0018] In the present invention, the oxidizing agent includes one or more of benzoyl peroxide, tert-butyl hydroperoxide, ammonium persulfate, and hydrogen peroxide;

[0019] The reducing agent includes one or more of N,N-dimethyl-p-toluidine, sodium metabisulfite, sodium bisulfite, and ferrous sulfate;

[0020] The molar ratio of the oxidizing agent to the cycloalkenone acetal compound is 0.001 - 0.2:1;

[0021] The molar ratio of the oxidizing agent to the reducing agent is 0.01 - 10:1.

[0022] The present invention provides a method for preparing the absorbable rapid hemostatic adhesive described in the above technical solution, including the following steps:

[0023] 1) Mix the cycloalkenone acetal compound and the oxidizing agent to obtain component A;

[0024] Mix the vinyl monomer, crosslinking agent, hemostatic agent, and reducing agent to obtain component B;

[0025] 2) Mix component A and component B evenly, and after in-situ curing, obtain the absorbable rapid hemostatic adhesive.

[0026] The present invention provides an application of the absorbable rapid hemostatic adhesive described in the above technical solution or the absorbable rapid hemostatic adhesive prepared by the preparation method described in the above technical solution in the preparation of hemostatic products.

[0027] In the present invention, the hemostatic site is the skin, internal organs, or blood vessels.

[0028] The present invention provides an absorbable rapid hemostatic adhesive, and the preparation raw materials include the following component A and component B: Component A includes a cycloalkenone acetal compound and an oxidizing agent; Component B includes a vinyl monomer, a crosslinking agent, a hemostatic agent, and a reducing agent. The adhesive provided by the present invention is formed by in-situ curing through free radical ring-opening polymerization under the initiation of an oxidation-reduction free radical polymerization initiator in the human body environment. It has a rapid bonding and closing, slightly exothermic reaction, and will not burn the human body; after the free radical ring-opening polymerization of the cycloalkenone acetal compound, the main chain contains an ester bond structure, which can degrade in the physiological environment, and the degradation rate at 8 weeks > 20%; the mild reaction conditions are conducive to the loading of the hemostatic agent and antibacterial agent. As these substances are gradually exposed and released, it further endows the adhesive with the activated hemostatic effect and avoids bacterial infection. The adhesive is prepared and used immediately, the use process is simple, the ideal operation time window is 1 - 5 minutes, and the clinical operability is strong. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the shear bonding model provided by the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention provides an absorbable and fast - hemostatic adhesive, and the preparation raw materials include the following component A and component B:

[0031] The component A includes cycloalkenone acetal compounds and oxidants;

[0032] The component B includes vinyl monomers, cross - linkers, hemostatic agents and reducing agents.

[0033] In the present invention, the cycloalkenone acetal compounds include one or more of 2 - methylene - 1,3 - dioxepane (MDO), 2 - methylene - 4 - phenyl - 1,3 - dioxolane (MPDL), 5,6 - benzo - 2 - methylene - 1,3 - dioxepane (BMDO) and 4,7 - dimethyl - 2 - methylene - 1,3 - dioxepane (DMMDO);

[0034] The 2 - methylene - 1,3 - dioxepane has the structure of formula 101:

[0035]

[0036] The 2 - methylene - 4 - phenyl - 1,3 - dioxolane has the structure of formula 102:

[0037]

[0038] The 5,6 - benzo - 2 - methylene - 1,3 - dioxepane has the structure of formula 103:

[0039]

[0040] The 4,7 - dimethyl - 2 - methylene - 1,3 - dioxepane has the structure of formula 104:

[0041]

[0042] The vinyl monomers include one or more of (meth)acrylic acid, (meth)acrylate, vinyl acetate, maleimide polyethylene glycol carboxylic acid, biotin-PEG-6-maleimide, m-maleimide benzoic acid succinimide ester, 6-maleimide hexanoic acid, ethylene glycol vinyl ether, tetraethylene glycol mono vinyl ether, ethylene (2-chloroethyl) ether, 2-methacryloyloxyethyl phosphorylcholine, 10-(2-methacryloyloxy) monodecyl phosphate, (meth)acryloyloxy sulfobetaine, 4-methacryloyloxyethyl trimellitic anhydride, methacryloyldopamine, N-acryloyl (trimethylol) aminomethane, polyethylene glycol methacrylate, N,N-dimethylaminoethyl methacrylate, (meth)allylamine, and O-allyl hydroxylamine. In a specific embodiment, the vinyl monomers are selected from methacrylic acid (MA), polyethylene glycol methacrylate (PEM), ethylene glycol vinyl ether, or 2-methacryloyloxyethyl phosphorylcholine.

[0043] In the present invention, the crosslinking agent is selected from monomers containing two vinyl units and / or monomers containing more than two vinyl units; the crosslinking agent is preferably selected from one or more of methacrylic anhydride, diallyl maleate, bis(methacryloyloxyethyl) hydrogen phosphate, tris(ethylene glycol) divinyl ether, diallylamine, triallylamine, N-methyldiallylamine, 1,5-hexadiene, diallyl disulfide, and diallyldimethylsilane. In a specific embodiment, the crosslinking agent is bis(methacryloyloxyethyl) hydrogen phosphate.

[0044] In the present invention, the hemostatic agent includes one or more of vitamin K1, vitamin K4, hemocoagulase, carbazochrome sodium sulfonate, aminocaproic acid, carbazochrome, and elo.

[0045] In the present invention, the molar ratio of the vinyl monomer and the cycloalkenone acetal compound is 0.01 - 100:1; preferably 0.1 - 0:1;

[0046] The molar ratio of the crosslinking agent and the cycloalkenone acetal compound is 0.001 - 0.2:1; preferably 0.005 - 0.05:1

[0047] The molar ratio of the hemostatic agent and the cycloalkenone acetal compound is 1×10 -7 ~1×10 -4 :1, preferably 1×10 -6 ~1×10 -5 :1.

[0048] The B component of the absorbable rapid hemostatic adhesive provided by the present invention preferably further includes an antibacterial agent; the antibacterial agent includes one or more of silver ions, zinc ions, antibacterial peptides, coumarin compounds, polyguanidine polymers, and benzalkonium chloride; the molar ratio of the antibacterial agent to the cycloalkenone acetal compound is 1×10 -7 ~1×10 -4 :1, preferably 1×10 -5 -1×10 -7 :1.

[0049] In the present invention, the oxidizing agent includes one or more of benzoyl peroxide, tert-butyl hydroperoxide, ammonium persulfate, and hydrogen peroxide;

[0050] The reducing agent includes one or more of N,N-dimethyl-p-toluidine, sodium metabisulfite, sodium bisulfite, and ferrous sulfate;

[0051] The molar ratio of the oxidizing agent to the cycloalkenone acetal compound is 0.001~0.2:1;

[0052] The molar ratio of the oxidizing agent to the reducing agent is 0.01~10:1.

[0053] The oxidizing agent is solid; the reducing agent is liquid.

[0054] The oxidizing agent in the A component and the reducing agent in the B component serve as an oxidation-reduction free radical polymerization initiator, and the in-situ curing is to carry out a ring-opening polymerization reaction; the ring-opening polymerization reaction is carried out under the initiation of the oxidation-reduction free radical polymerization initiator.

[0055] The present invention provides a preparation method of the absorbable rapid hemostatic adhesive described in the above technical solution, including the following steps:

[0056] 1) Mix the cycloalkenone acetal compound and the oxidizing agent to obtain the A component;

[0057] Mix the vinyl monomer, crosslinking agent, hemostatic agent, and reducing agent to obtain the B component;

[0058] 2) Mix the A component and the B component evenly, and after in-situ curing, obtain the absorbable rapid hemostatic adhesive.

[0059] In the present invention, the mixing time of the A component and the B component is preferably 1~300 s, more preferably 5~20 s.

[0060] After the A component and the B component are mixed, the system undergoes an in-situ free radical ring-opening polymerization reaction. The temperature of the polymerization reaction is 30~50 °C, preferably 35~38 °C. The polymerization reaction is a ring-opening polymerization reaction with free radicals as the active centers. The main chain of the component free radical polymerization contains an ester bond structure.

[0061] To improve the antibacterial effect, the present invention preferably adds an antibacterial agent to component B.

[0062] The adhesive provided by the present invention comprises component A and component B. When coated on the wounds or surgical incisions of tissue organs and skin, after mixing component A and component B and quickly coating them, an in-situ free radical ring-opening polymerization reaction occurs rapidly, achieving rapid adhesion and closure of the wounds or surgical incisions.

[0063] In the present invention, the coating time is preferably 1 - 600 s, more preferably 1 - 100 s, and even more preferably 1 - 30 s.

[0064] The present invention provides an application of the absorbable rapid hemostatic adhesive as described in the above technical solution or the absorbable rapid hemostatic adhesive prepared by the preparation method as described in the above technical solution in the preparation of hemostatic products.

[0065] In the present invention, the hemostatic site is skin, organ or blood vessel.

[0066] The present invention adds an oxidation-reduction free radical polymerization initiator to the above substance mixture, coats it on bleeding sites such as blood vessels, organs and skin, and after an in-situ free radical ring-opening polymerization reaction occurs rapidly, rapid closure hemostasis is achieved. The preparation method of the hemostatic adhesive is simple, it can be used immediately after preparation, the bleeding opening has a fast adhesion and closure speed, the hemostasis speed is fast, closure hemostasis can be achieved within 15 s, the biodegradability is excellent, and the antibacterial agent is released as the adhesive degrades, avoiding the occurrence of bacterial infection.

[0067] To further illustrate the present invention, the following examples are used to describe in detail an absorbable rapid hemostatic adhesive provided by the present invention, its preparation method and application, but they should not be construed as limiting the protection scope of the present invention.

[0068] In the following examples, the added molar percentages of the cross-linking agent, hemostatic agent, oxidizing agent and reducing agent are all based on the molar amount of the cycloalkenone acetal compound.

[0069] Example 1

[0070] Dissolve 2,5 - hexanediol (1.2 g, 10.2 mmol) in dichloromethane (170 ml) and pyridine (7.5 ml, 91.5 mmol). Place the reaction system in an argon - purged environment at - 20 °C. Then, drop - wise add a solution of triphosgene (4.55 g, 15.2 mmol) in dichloromethane (90 ml). After the addition is complete, warm the reaction mixture to room temperature and react for 20 min. Then, quench the reaction with saturated ammonium chloride solution (100 ml). Extract the product mixture with dichloromethane. Wash the obtained organic phase with saturated brine, dry it over anhydrous sodium sulfate, filter, and remove the solvent under vacuum. Perform vacuum distillation and collect the fraction around 95 °C. Dissolve the product obtained above (0.023 g, 0.16 mmol) in a mixed solvent of tetrahydrofuran / toluene (1:1). Add Petasis reagent (2 ml, 0.5 mmol, a 5 wt% tetrahydrofuran / toluene mixed solution). Purge the reaction system with argon and react under light - free conditions at 60 - 65 °C for 20 h. After the reaction is completed, add n - hexane (10 ml) to form a yellow precipitate. Filter and concentrate the filtrate to obtain the product DMMDO.

[0071] Mix 0.1 mol of the cycloalkenone compound DMMDO with benzoyl peroxide (BPO, 2 mol%). Obtain Component A; Mix 0.2 mol of the comonomer methacrylic acid (MA), 0.05 mol% of the cross - linker bis(2 - methacryloyloxyethyl) hydrogen phosphate, 1×10 -5 mol% of halloysite, 1×10 -5 mol% of benzalkonium chloride, and N,N’ - dimethyl - p - toluidine (DMPT, 2 mol%). After mixing evenly, reserve it as Component B. Quickly and evenly mix Component A and Component B. Quickly and evenly coat the obtained mixture on the application site or in a polytetrafluoroethylene mold, and carry out free - radical ring - opening polymerization adhesion at room temperature.

[0072] Example 2

[0073] 2-Bromo-1,1'-dimethoxyethane (65 g, 0.4 mol), 1,4-butanediol (36 g, 0.51 mol) and Dowex 50 acidic ion exchange resin (0.5 g) were added to a reaction flask. The reaction temperature was set at 115 °C. During the reaction, the by-product methanol was continuously collected using a water separator, and the reaction progress was judged according to the amount of methanol collected. The reaction continued for about 4 h. After the reaction was completed, the acidic resin was removed by filtration. The obtained crude product was subjected to vacuum distillation, and the fraction at 95 °C was collected; the product obtained above (35 g, 0.18 mol) was dissolved in 70 ml of dry tetrahydrofuran and placed in a reaction flask. Aliquat 336 (1.67 g, 0.004 mol) was added, the reaction temperature was lowered to 0 °C, and t-BuOK (40.41 g, 0.36 mol) was gradually added. The temperature was maintained for reaction for 2 h. After the reaction was completed, the solid was removed by filtration, the organic phase was concentrated, and the obtained crude product was distilled, and the fraction at 25 °C was collected to obtain the product MDO.

[0074] 0.1 mol of the cycloalkenone compound MDO was mixed with benzoyl peroxide (BPO, 2 mol%). Component A was obtained; 0.02 mol of the comonomer polyethylene glycol methacrylate (PEM), 0.04 mol% of the crosslinking agent bis(2-methacryloyloxyethyl) hydrogen phosphate, 5×10 -6 mol% of hemocoagulase, 1×10 -6 mol% of polyhexamethylene biguanide hydrochloride and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%) were mixed evenly and used as Component B for standby; Component A and Component B were quickly and evenly mixed, and the obtained mixed solution was quickly and evenly coated at the application position, and free radical ring-opening polymerization adhesion occurred at room temperature.

[0075] Example 3

[0076] 2-Bromo-1,1'-dimethoxyethane (65 g, 0.4 mol), o-phthalic alcohol (69 g, 0.5 mol) and Dowex 50 acidic ion exchange resin (0.5 g) were added to a reaction flask. The reaction temperature was set at 120 °C. During the reaction, the by-product methanol was continuously collected using a water separator, and the reaction progress was judged according to the amount of methanol collected. The reaction lasted for about 8 h. After the reaction was completed, the acidic resin was removed by filtration. The obtained crude product was subjected to vacuum distillation, and the fraction around 160 °C was collected; the product obtained above (43.77 g, 0.18 mol) was dissolved in 70 ml of dry tetrahydrofuran and placed in a reaction flask. Aliquat 336 (1.67 g, 0.004 mol) was added, the reaction temperature was lowered to 0 °C, and t-BuOK (40.41 g, 0.36 mol) was gradually added. The temperature was maintained for 2 h. After the reaction was completed, the solid was removed by filtration, the organic phase was concentrated, and the obtained crude product was distilled. The fraction around 96 - 99 °C was collected to obtain the product BMDO.

[0077] 0.1 mol of the cycloalkenone compound BMDO was mixed with benzoyl peroxide (BPO, 2 mol%); 0.1 mol of the comonomer methacrylic acid (MA), 0.03 mol% of bis(2-methacryloyloxyethyl) hydrogen phosphate crosslinking agent, 3×10 -6 mol% of 6-aminocaproic acid, 5×10 -7 mol% of antimicrobial peptide and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%) were mixed evenly and used as component B; component A and component B were quickly and evenly mixed; the obtained mixed solution was quickly and evenly coated at the application position, and free radical ring-opening polymerization adhesion occurred at room temperature.

[0078] Example 4

[0079] 2-Bromo-1,1'-dimethoxyethane (65 g, 0.4 mol), 1-phenyl-1,2-ethanediol (69 g, 0.5 mol) and Dowex 50 acidic ion exchange resin (0.5 g) were added to a reaction flask. The reaction temperature was set at 120 °C. During the reaction, the by-product methanol was continuously collected using a water separator, and the reaction progress was judged according to the amount of methanol collected. The reaction continued for about 4 h. After the reaction was completed, the acidic resin was removed by filtration. The obtained crude product was subjected to vacuum distillation, and the fraction around 70 °C was collected; the product obtained above (43.77 g, 0.18 mol) was dissolved in 70 ml of dry tetrahydrofuran and placed in a reaction flask. Aliquat 336 (1.67 g, 0.004 mol) was added. The reaction temperature was lowered to 0 °C, and t-BuOK (40.41 g, 0.36 mol) was gradually added. The temperature was maintained for 2 h. After the reaction was completed, the solid was removed by filtration. The organic phase was concentrated, and the obtained crude product was distilled. The fraction around 50 °C was collected to obtain the product MPDL.

[0080] 0.1 mol of the cycloalkenone compound MPDL was mixed with benzoyl peroxide (BPO, 2 mol%), to obtain Component A; 0.01 mol of the comonomer polyethylene glycol methacrylate was mixed evenly. The mixture gave off a slight heat, and then 0.01 mol% of bis(2-methacryloyloxyethyl) hydrogen phosphate crosslinking agent, 2×10 -6 mol% of vitamin K1, 3×10 -7 mol% of silver ions and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%) were added and mixed evenly. After that, it was reserved as Component B; Component A and Component B were quickly and evenly mixed, and the obtained mixture was quickly and evenly coated at the application position, and radical ring-opening polymerization adhesion occurred at room temperature.

[0081] Example 5

[0082] The preparation process of DMMDO was the same as that in Example 1.

[0083] 0.1 mol of the cycloalkenone compound DMMDO was mixed with benzoyl peroxide (BPO, 2 mol%) to obtain Component A; 0.05 mol of ethylene glycol vinyl ether (EGVE), 0.05 mol% of bis(2-methacryloyloxyethyl) hydrogen phosphate crosslinking agent, 2×10 -6 mol% of vitamin K4, 2×10 -7 mol% of coumarin and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%) were added and mixed evenly. After that, it was reserved as Component B; Component A and Component B were quickly and evenly mixed, and the obtained mixture was quickly and evenly coated at the application position or in a polytetrafluoroethylene mold, and radical ring-opening polymerization adhesion occurred at room temperature.

[0084] Example 6

[0085] The preparation process of MDO is the same as that in Example 2.

[0086] Mix 0.1 mol of cycloalkenone compound MDO with benzoyl peroxide (BPO, 2 mol%) to obtain Component A; mix 0.03 mol of comonomer 2-methacryloyloxyethyl phosphorylcholine (MPC), 0.04 mol% of bis(methacryloyloxyethyl) hydrogen phosphate crosslinking agent, 3×10 -6 mol% of carbazochrome sodium sulfonate, 3×10 -7 mol% of polyhexamethylene guanidine hydrochloride and N,N'-dimethyl-p-toluidine (DMPT, 2 mol%), and after mixing evenly, reserve it as Component B; quickly and evenly mix Component A and Component B, and quickly and evenly coat the obtained mixture on the application position, and carry out free radical ring-opening polymerization adhesion at room temperature.

[0087] Comparative Example 1

[0088] Quickly and evenly coat a mixture of 10 g of 2-octyl cyanoacrylate (OCA) and 5 mg of p-toluenesulfonic acid (PTSA, stabilizer) on the degreased pigskin, cover another piece of pigskin on it, gently press for 20 s, and carry out in-situ polymerization reaction at room temperature to achieve adhesion.

[0089] Comparative Example 2

[0090] Mix 10 g of cycloalkenone compound DMMDO with comonomer methacrylic acid (MA, 7.5 g) evenly, the mixture slightly exotherms, then add 0.05 mol% of bis(methacryloyloxyethyl) hydrogen phosphate crosslinking agent and mix evenly for standby; fully dissolve benzoyl peroxide (BPO, 2 mol%) in the above mixture, then add N,N'-dimethyl-p-toluidine (DMPT, 2 mol%), and mix quickly and evenly; quickly and evenly coat the mixture on the application position, and carry out free radical ring-opening polymerization adhesion at room temperature.

[0091] Test Experiment

[0092] 1. In vitro adhesion experiment

[0093] According to the GB / T 7124-2008 standard, the in vitro adhesion strength is obtained through shear adhesion test, and the shear adhesion model is as Figure 1As shown. Before the experiment, the fat-free pigskin was selected and cut into regular plate-shaped splines. The length and width of the splines were 10 cm × 2.5 cm, and the thickness was 0.2 cm. It was prepared as described in Examples 1-6 and Comparative Example 1, and the bonding area was 2.5 cm × 1.0 cm. After the prepared bonding samples were placed at room temperature for 2 h, tensile tests were carried out on a universal testing machine (LD-5 type of LLOYD company, the sensor was 2.5 kN), the tensile rate was 5 mm / min, and the shear bond strength was calculated by dividing the load force at the fracture of the bonding sample by the bonding area.

[0094] Table 1 In vitro bond strength (MPa)

[0095] Experimental grouping Comparative example 1 Comparative example 2 Example 1 Example 2 Bonding strength 1.6±0.2 1.7±0.3 1.7±0.4 1.3±0.2 Experimental grouping Example 3 Example 4 Example 5 Example 6 Bonding strength 1.5±0.2 1.4±0.3 1.2±0.3 1.3±0.4

[0096] It can be seen from Table 1 that the bond strengths of the materials in Examples 1-6 are all above 1 MPa, and the maximum bond strength of Example 1 exceeds that of Comparative Example 1, showing good bonding performance. This is because the preferred methacrylic acid can improve the polarity and hydrophilicity of the material, increase the contact and infiltration with tissues, and thus improve the bond strength.

[0097] 2. In vitro coagulation experiment

[0098] The whole blood used in the experiment was rabbit whole blood containing 10% (mass fraction) sodium citrate anticoagulant. The polymers prepared in Examples 1-6 and Comparative Examples 1-2 were respectively placed in a polytetrafluoroethylene mold for curing and forming, and then 0.1 g was weighed for standby. 1 ml of fresh rabbit whole blood containing anticoagulant and 0.1 g of the sample were placed in a centrifuge tube and incubated at 37 °C for 5 minutes, 100 μL of calcium chloride solution with a concentration of 0.025 mol / L was added and mixed evenly, and the timing was started immediately. The centrifuge tube was inverted every 5 seconds, and the timing was stopped when the blood no longer flowed down, and the blood coagulation time was recorded. The results are shown in Table 2.

[0099] Table 2 Statistical results data table of in vitro coagulation time (s)

[0100] Experimental grouping Negative control Comparative example 1 Comparative example 2 Example 1 Example 2 Coagulation time 600±10 400±15 410±10 35±5 30±10 Experimental grouping Example 3 Example 4 Example 5 Example 6 Coagulation time 40±5 35±15 40±5 45±5

[0101] The results of the in vitro coagulation time are shown in Table 2, where the negative control group was the blood with only 100 μL of calcium chloride solution with a concentration of 0.025 mol / L added. Compared with Comparative Example 1 and Comparative Example 2, the blood coagulation time in Examples 1-6 decreased significantly. This is because hemostatic agents such as halloysite, hemocoagulase, aminocaproic acid, and vitamin K1 were added in Examples 1-6. These hemostatic agents can better promote blood coagulation after contacting with the blood, significantly shorten the in vitro coagulation time, and enable the adhesive to play a rapid hemostasis function while sealing the wound.

[0102] 3. In vitro antibacterial experiment

[0103] The polymers prepared in Examples 1-6 and Comparative Examples 1-2 were respectively placed in a polytetrafluoroethylene mold for curing and forming, and then cut into 1.5 cm × 1.5 cm square samples for standby. According to the requirements for antibacterial performance evaluation in the GB / T 31402 standard, Staphylococcus aureus and Escherichia coli were selected as test strains, and the square samples prepared in Examples 1-6 and Comparative Examples 1-2 were subjected to antibacterial performance tests in strict accordance with the experimental steps described in the GB / T 31402 standard.

[0104] Table 3 Bactericidal rates (%) against Staphylococcus aureus and Escherichia coli

[0105]

[0106]

[0107] The results of the in vitro antibacterial experiment are shown in Table 3. After adding antibacterial agents benzalkonium bromide, polyhexamethylene guanidine, antibacterial peptides, and silver ions in Examples 1-6, the bactericidal rates against Staphylococcus aureus and Escherichia coli can reach over 95%, indicating that the adhesives prepared in Examples 1-6 have obvious bactericidal effects on both Gram-negative bacteria and Gram-positive bacteria.

[0108] 4. Hemostasis experiment on rat liver

[0109] The present invention conducted in vivo hemostasis function detection on the polymers obtained in Examples 1-6 and Comparative Examples 1-2. The specific detection method is as follows:

[0110] Using the liver hemorrhage of SD rats as a model, the rats were anesthetized by induction with 5% isoflurane and maintained with 1.5% isoflurane. The abdominal hair of the rats was shaved off, the abdominal cavity of the rats was opened along the ventral white line, the rat liver was found and exposed, a 0.5 cm wound was made on the left liver lobe with a scalpel, and the sample after equal-volume mixing was dropped on the surface of the liver wound, and the hemostasis situation was observed and the bleeding time was recorded.

[0111] Table 4 Hemostasis time (s) of the rat liver hemorrhage model

[0112] Experimental grouping Blank control Comparative example 1 Comparative example 2 Example 1 Example 2 Hemostasis time 350±20 220±15 160±10 40±5 35±5 Experimental grouping Example 3 Example 4 Example 5 Example 6 Hemostasis time 45±5 40±10 45±10 50±5

[0113] The hemostasis time results of the rat liver bleeding model are shown in Table 4, where the blank control group is the untreated rat liver bleeding model. After gelation and curing, the bleeding conditions of the rat liver in Comparative Example 1 and Comparative Example 2 were alleviated, which may be due to the sealing effect of the adhesive after curing. More preferably, the time taken for Examples 1 to 6 to stop bleeding in the rat liver was significantly lower than that of Comparative Examples 1 to 2. This may be because, on the basis of sealing the wound, the hemostatic agents added in Examples 1 to 6, such as halloysite, hemocoagulase, aminocaproic acid, and vitamin K1, can activate the coagulation cascade reaction after contacting with blood, promoting blood coagulation faster, enabling the adhesives prepared in Examples 1 to 6 to exert a rapid hemostasis function while sealing the wound.

[0114] As can be seen from the above examples, the present invention provides an absorbable and rapid hemostatic adhesive, and the preparation raw materials include the following Component A and Component B: Component A includes cycloalkenone acetal compounds and oxidants; Component B includes vinyl monomers, crosslinking agents, hemostatic agents, and reducing agents. The adhesive provided by the present invention is formed by in-situ curing of free radical ring-opening polymerization under the initiation of an oxidation-reduction free radical polymerization initiator in a human body environment. It has a rapid bonding and closing, slightly exothermic reaction, and will not burn the human body; the main chain of the cycloalkenone acetal compound contains an ester bond structure after free radical ring-opening polymerization and can degrade in a physiological environment, with a degradation rate of >20% at 8 weeks; the mild reaction conditions are conducive to the loading of hemostatic agents and antibacterial agents. As these substances are gradually exposed and released, it further endows the adhesive with the effect of activating hemostasis and avoids bacterial infection. This adhesive is used immediately after preparation, with a simple usage process. The ideal operation time window is 1 to 5 minutes, and it has strong clinical operability.

[0115] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. An absorbable and rapidly hemostatic adhesive, the preparation raw materials of which include the following component A and component B: The component A includes cycloalkenone acetal compounds and oxidants; the cycloalkenone acetal compounds include one or more of 2-methylene-1,3-dioxepane, 2-methylene-4-phenyl-1,3-dioxolane, 5,6-benzo-2-methylene-1,3-dioxepane, and 4,7-dimethyl-2-methylene-1,3-dioxepane; the oxidant is benzoyl peroxide; The component B includes vinyl monomers, crosslinking agents, hemostatic agents, and reducing agents; The vinyl monomers are selected from methacrylic acid, polyethylene glycol methacrylate, ethylene glycol vinyl ether, or 2-methacryloyloxyethyl phosphorylcholine; The crosslinking agent is bis(2-methacryloyloxyethyl) hydrogen phosphate; The reducing agent is N,N-dimethyl-p-toluidine; The molar ratio of the vinyl monomers to the cycloalkenone acetal compounds is 0.01~100:

1.

2. The absorbable and rapidly hemostatic adhesive according to claim 1, wherein The molar ratio of the crosslinking agent to the cycloalkenone acetal compounds is 0.001~0.2:1; The molar ratio of the hemostatic agent to the cycloalkenone acetal compound is 1×10 -7 ~1×10 -4 :

1.

3. The absorbable rapid hemostatic adhesive according to claim 1, wherein The component B further includes antibacterial agents; the antibacterial agents include one or more of silver ions, zinc ions, antibacterial peptides, coumarin compounds, polyguanidine polymers, and benzalkonium chloride; The molar ratio of the antibacterial agent and the cycloalkenone acetal compound is 1×10 -5 ~1×10 -4 :

1.

4. The absorbable rapid hemostatic adhesive according to claim 1, wherein The hemostatic agents include one or more of vitamin K1, vitamin K4, hemocoagulase, carbazochrome sodium sulfonate, aminocaproic acid, carbazochrome, and elotuzumab.

5. The absorbable fast hemostatic adhesive according to claim 1, wherein, The molar ratio of the oxidant to the cycloalkenone acetal compounds is 0.001~0.2:1; The molar ratio of the oxidant to the reducing agent is 0.01~10:

1.

6. A preparation method of the absorbable and rapidly hemostatic adhesive according to any one of claims 1~5, comprising the following steps: 1) Mix the cycloalkenone acetal compounds and the oxidant to obtain the component A; Mix the vinyl monomers, the crosslinking agent, the hemostatic agent, and the reducing agent to obtain the component B; 2) Mix the component A and the component B evenly, and after in-situ curing, obtain the absorbable and rapidly hemostatic adhesive.

7. Use of the absorbable and rapidly hemostatic adhesive according to any one of claims 1~5 or the absorbable and rapidly hemostatic adhesive prepared by the preparation method according to claim 6 in the preparation of hemostatic products.

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