Preparation method of implantable cyanoacrylate medical adhesive and application thereof

Abstract

The application discloses a preparation method of an implantable cyanoacrylate medical adhesive and application thereof, and belongs to the technical field of medical polymer material purification, and aims to solve the technical problems of easy monomer polymerization caused by high temperature, poor selectivity of impurity removal, excessive solvent residue, substandard biocompatibility, waste of by-products, poor batch stability and difficulty in realizing implant-grade purity in the existing cyanoacrylate medical adhesive purification process. The method comprises the following steps: low-temperature supercritical gradient extraction, selective adsorption refining, membrane separation impurity removal, by-product resource modification and finished product preparation. The low-temperature purification process below 40 DEG C is adopted throughout the application, the traditional high-temperature distillation and recrystallization process is abandoned, the self-polymerization of cyanoacrylate monomers caused by heat is avoided from the root, the effective monomer content of the finished product is ensured to be stable, the curing performance is uniform, the problem of high-temperature damage to the stability of monomers in the existing process is solved, the risk of high-temperature polymerization is eliminated, and the stability of the medical adhesive is greatly improved.

Description

Technical Field

[0001] This invention belongs to the field of medical polymer material purification technology, specifically relating to a purification and preparation method of implantable cyanoacrylate medical adhesive, and the application of this preparation method in the field of implantable medical adhesives. Background Technology

[0002] Cyanoacrylate medical adhesives are widely used in medical applications such as surgical incision bonding, hemostasis of internal organ wounds, and tissue repair due to their advantages of fast curing speed, high bonding strength, and no need for additional curing equipment. In particular, implantable cyanoacrylate medical adhesives have strict implantable medical standards for purity, biocompatibility, and chemical stability, and are one of the core research and development directions in the field of biomedical adhesives.

[0003] Existing purification processes for cyanoacrylates mostly employ conventional methods such as recrystallization, atmospheric distillation, vacuum distillation, and organic solvent extraction. These methods remove impurities such as monomer residues, organic acids, moisture, and polymers from the crude product through steps including solvent dissolution, temperature separation, and solid-liquid separation, thereby improving the purity of the cyanoacrylate to meet basic medical requirements. Some processes may supplement these with auxiliary methods such as single-solvent extraction and simple filtration to further reduce the impurity content in the crude product.

[0004] However, the existing purification techniques mentioned above have many insurmountable drawbacks: 1. Traditional recrystallization and distillation processes require high-temperature heating or the use of highly polar organic solvents. However, cyanoacrylate monomers are chemically active and are prone to self-polymerization in high-temperature environments, resulting in a decrease in the effective monomer content and poor curing performance of the finished product. At the same time, the residue of strong solvents will significantly reduce the biocompatibility of medical adhesives and fail to meet the safety requirements for implantation. 2. Conventional purification methods have poor selectivity in removing impurities, making it difficult to accurately target and remove key impurities such as polymerization inhibitors, trace metal ions, and organic byproducts. The purity after purification is difficult to reach the implantable grade standard of 99.99%, and residual impurities can easily cause rejection and inflammatory reactions in the body. 3. The purification process is mostly an intermittent operation, with the purification and stabilization processes being separate, resulting in large batch variations. Furthermore, the oligomer byproducts generated during purification are mostly discarded as waste, causing both resource waste and environmental pollution. 4. Conventional purification processes consume a lot of energy and lose a lot of solvent, resulting in high purification costs, which makes them difficult to adapt to large-scale medical production. Summary of the Invention

[0005] This invention addresses the shortcomings of existing technologies by solving technical problems in the purification process of cyanoacrylate medical adhesives, such as high-temperature-induced monomer polymerization, poor selectivity in impurity removal, excessive solvent residue, substandard biocompatibility, waste of by-products, poor batch stability, and difficulty in achieving implantable-grade purity. It provides a preparation method and application that is suitable for implantation, high in purity, low in residue, environmentally friendly, and highly stable.

[0006] Therefore, the specific technical solution adopted by the present invention is as follows: According to one aspect of the present invention, a method for preparing implantable cyanoacrylate medical adhesive is provided, comprising the following steps: S1, Low-temperature supercritical Gradient extraction: Crude cyanoacrylate is added to a supercritical extraction vessel, sealed, and then purged with medical-grade cyanoacrylate. The extraction temperature was controlled below 40℃, and a multi-stage pressure gradient was set for stepwise extraction to remove impurities of different polarities step by step. The pre-purified solution was obtained by depressurization separation. S2. Selective adsorption purification: The preliminary purified solution obtained in step S1 is passed into a solid phase extraction column, and residual polymerization inhibitor impurities are removed by specific adsorption to obtain a purified solution. S3. Membrane separation and impurity removal: The purified solution obtained in step S2 is passed through a nanofiltration membrane to remove macromolecular polymer impurities and obtain high-purity cyanoacrylate monomer. S4. By-product resource utilization and modification: Collect the oligomer by-products generated during the extraction process in step S1, and prepare them into bioactive functional fillers through hydrolysis and surface modification. S5. Finished product preparation: The functional filler obtained in step S4 is re-mixed into the high-purity cyanoacrylate monomer obtained in step S3 in a certain proportion, and the mixture is mixed to obtain implantable cyanoacrylate medical adhesive.

[0007] Optionally, step S1 specifically includes: S11, Low-pressure extraction: Control the extraction pressure to 8MPa and extract for 25-30min to remove unreacted monomers and other low-polarity impurities from the crude product; S12, Medium-pressure extraction: Increase the pressure to 15MPa and extract for 35-40 minutes. At the same time, add 0.5% by volume of medical ethanol as an entrainer to remove water and polar impurities such as organic acids. S13, High-pressure recovery: Increase the pressure to 25MPa, extract for 45-50min, recover the high-purity cyanoacrylate component, and obtain the preliminary purified solution.

[0008] Optionally, in step S2, the solid-phase extraction column is filled with a molecularly imprinted polymer, which is prepared by polymerization using hydroquinone as a template molecule and methacrylic acid as a functional monomer. The flow rate of the purification solution is controlled at 0.8-1.2 mL / min, and the hydroquinone polymerization inhibitor is specifically adsorbed and removed. After elution, the residual polymerization inhibitor is less than 0.1 ppm.

[0009] Optionally, in step S3, the nanofiltration membrane is a modified polyethersulfone nanofiltration membrane with a molecular weight cutoff of 200 Da. Filtration is performed at room temperature and pressure to completely remove macromolecular polymer impurities in the system while retaining small molecule cyanoacrylate monomers.

[0010] Optionally, step S4 specifically includes: S41. The collected oligomer byproducts are placed in a weakly alkaline solution and hydrolyzed at a constant temperature for 2-3 hours to obtain polycyanoacrylate nanoparticles. S42. The nanoparticles are modified with amino or carboxyl groups to obtain antibacterial and procoagulant functional fillers with a particle size of 50-100 nm.

[0011] Optionally, in step S5, the re-addition mass ratio of the functional filler is 0.1-1 wt%.

[0012] Optionally, after extraction and separation in step S1, the cyanoacrylate obtained has a purity of not less than 99.99% and a residual solvent content of less than 10 ppm.

[0013] Optionally, the molecularly imprinted polymer can be reused after being eluted and regenerated with a methanol / water mixture.

[0014] Optionally, the application of a method for preparing an implantable cyanoacrylate medical adhesive is used to prepare an implantable surgical adhesive, an in vivo wound hemostasis adhesive, or a soft tissue repair cyanoacrylate medical adhesive.

[0015] Compared with the prior art, this application has the following beneficial effects: 1. This invention employs a low-temperature purification process below 40°C throughout, abandoning the traditional high-temperature distillation and recrystallization process. This fundamentally avoids the self-polymerization of cyanoacrylate monomers due to heat, ensuring stable effective monomer content and uniform curing performance in the finished product. It solves the problem of high-temperature degradation of monomer stability in existing processes, eliminates the risk of high-temperature polymerization, and significantly improves the stability of medical adhesives.

[0016] 2. Through supercritical fluid gradient extraction, molecular imprinted selective adsorption, and membrane separation in a multi-stage process, low-polarity impurities are removed under low pressure, water and organic acids are removed under medium pressure, and high-purity monomers are recovered under high pressure. At the same time, targeted removal of polymerization inhibitor residues is achieved. The purified cyanoacrylate has higher purity, less residual solvent, and less residual polymerization inhibitor, which fully meets the biocompatibility requirements of implantable medical materials, avoiding inflammation and rejection reactions in the body. The impurity removal is precise and efficient, and the implantable purity meets the standards.

[0017] 3. The oligomer waste generated during purification is transformed in situ into bioactive functional fillers, turning waste into treasure. This not only reduces industrial waste emissions and environmental pollution, but also endows medical adhesives with additional antibacterial and hemostatic functions, increasing product added value. At the same time, it reduces the overall purification cost, realizes the resource utilization of by-products, and achieves green cost reduction.

[0018] 4. It can realize integrated continuous operation of purification, stabilization and functional modification, reduce pollution and loss caused by process flow, significantly reduce batch differences, improve product quality uniformity, adapt to industrial-scale production, have strong process continuity and good batch stability. Attached Figure Description

[0019] The above-mentioned features, characteristics, and advantages of the present invention, as well as their implementation methods, will become clearer and more readily understood in conjunction with the following description of the embodiments, which are illustrated in detail with reference to the accompanying drawings. Schematic diagrams are shown here: Figure 1 This is a flowchart of a method for preparing implantable cyanoacrylate medical adhesive according to an embodiment of the present invention. Detailed Implementation

[0020] The present invention will be further described in detail below with reference to specific embodiments. These embodiments are only used to explain the present invention and are not intended to limit the scope of protection of the present invention. The raw materials and reagents used in the present invention are all commercially available medical-grade products, and the detection methods are conventional standard methods in the art.

[0021] Example 1 A method for preparing implantable cyanoacrylate medical adhesive, comprising the following steps: (1) Low-temperature supercritical fluid gradient extraction: 100g of crude cyanoacrylate was placed in a high-pressure sealed supercritical extraction vessel, and after sealing and leak testing, medical-grade fluid was introduced. The extraction temperature is strictly controlled at 35℃, which is below the self-polymerization critical temperature of cyanoacrylate monomers, thus preventing the monomers from undergoing thermal polymerization at the source. A three-stage gradient pressure extraction method is used: S11, low-pressure extraction: maintaining a pressure of 8MPa and constant temperature extraction for 30 minutes, utilizing supercritical fluid extraction under low pressure. Its weak solubility removes unreacted small molecule monomers and low-polarity alkanes from the crude product; S12, medium-pressure extraction: pressurize to 15 MPa, extract at a constant temperature for 40 min, and simultaneously add 0.5% by volume of medical ethanol as a biocompatible entrainer to enhance supercritical extraction. It has the ability to dissolve polar impurities such as water and free organic acids, and completely removes polar impurities that affect biocompatibility; S13, high pressure recovery: continue to increase the pressure to 25MPa, extract at a constant temperature for 50min, fully dissolve the high-purity cyanoacrylate monomer, slowly depressurize and desorb to obtain a preliminary purified solution.

[0022] (2) Molecularly imprinted selective adsorption: Molecularly imprinted polymer was prepared in advance: hydroquinone was used as the template molecule, methacrylic acid was used as the functional monomer, ethylene glycol dimethacrylate was used as the crosslinking agent, and azobisisobutyronitrile was used as the initiator. The molar ratio of template molecule, functional monomer and crosslinking agent was 1:4:20. The amount of initiator added was 0.8% of the total mass of the reaction system. Acetonitrile was used as the reaction solvent. The polymer was stirred and polymerized at 60℃ for 8h. After the polymerization was completed, a methanol / glacial acetic acid mixture with a volume ratio of 9:1 was used as the eluent. The polymer was continuously extracted by Soxhlet extraction for 24h to completely elute the template molecule hydroquinone. After the eluent was completed, the polymer was placed in a vacuum drying oven at 60℃ and dried to constant weight to obtain molecularly imprinted polymer microspheres. The microspheres were then filled into a solid phase extraction column for later use.

[0023] Template molecule elution verification: The eluent was detected by high performance liquid chromatography (HPLC). The detection conditions were set as follows: mobile phase methanol:water volume ratio = 60:40, flow rate 1 mL / min, detection wavelength 275 nm. When the characteristic peak area of ​​hydroquinone in the eluent was less than 0.01 AU, the template molecule was determined to be completely eluted and without residue.

[0024] The pre-purified solution was passed into a solid-phase extraction column filled with a molecularly imprinted polymer (MIRP). This polymer, synthesized using hydroquinone as a template molecule and methacrylic acid as a functional monomer, exhibits specific adsorption properties for polymerization inhibitors. The flow rate was controlled at 1 mL / min to specifically adsorb and remove residual hydroquinone polymerization inhibitors. Impurities were eluted using a methanol / water mixture with a volume ratio of 9:1 to regenerate the adsorbent. The regenerated MIRP can be reused more than 50 times without significant degradation in adsorption performance. Product verification after adsorption: Under the same HPLC detection conditions, the residual amount of polymerization inhibitor was measured to be 0.08 ppm, less than 0.1 ppm, meeting the standards for implantable medical applications.

[0025] (3) Nanofiltration membrane purification: The filtrate after adsorption is passed through a modified polyethersulfone nanofiltration membrane with a molecular weight cutoff of 200 Da at room temperature and pressure. The molecular weight of the cyanoacrylate monomer is less than 200 Da, so it can pass through the membrane pores smoothly, while the large molecular impurities generated by polymerization cannot pass through and are completely retained, thereby further improving the purity of the monomer and obtaining high-purity cyanoacrylate monomer.

[0026] (4) Resource utilization of by-products: Collect the oligomer by-products remaining at the bottom of the extraction vessel and place them in a weakly alkaline solution (the weakly alkaline solution is medical-grade sodium bicarbonate solution, with the pH value controlled at 8.5-9.5, which can gently hydrolyze the oligomers without destroying the structural stability of cyanoacrylate), and hydrolyze at a constant temperature of 45℃ for 2 hours to prepare polycyanoacrylate nanoparticles with uniform particle size, with the particle size controlled at 50-100nm; perform amino surface modification on the nanoparticles, the specific modification method being: disperse the nanoparticles in anhydrous ethanol. Add 3-aminopropyltriethoxysilane (5% of the nanoparticle mass), stir at 60℃ for 4 hours, centrifuge after reaction, wash three times with anhydrous ethanol, and vacuum dry at 60℃ to constant weight to obtain amino-modified nano-functional filler; if carboxyl surface modification is used, the nanoparticles can be reacted with succinic anhydride, specifically: disperse the nanoparticles in dichloromethane, add succinic anhydride (molar ratio of nanoparticles: succinic anhydride = 1:2), stir at room temperature for 6 hours, centrifuge, wash and dry to obtain carboxyl-modified filler.

[0027] Antibacterial and Procoagulant Function Description: The technical principle involves amino- or carboxyl-modified polycyanoacrylate nanoparticles that can adsorb bacterial cell membranes through electrostatic interactions, disrupting bacterial integrity and thus achieving an antibacterial effect. Simultaneously, the modified nanoparticles can activate coagulation factor XII, accelerate platelet aggregation, and shorten clotting time, achieving a procoagulant function. Performance Testing Data: Antibacterial performance was tested using the agar diffusion method. The inhibition zone diameters against *Escherichia coli* and *Staphylococcus aureus* were 18.2 mm and 17.5 mm, respectively, with antibacterial rates ≥99%. Procoagulant performance was tested using prothrombin time (PT). The clotting time of the medical adhesive with added functional filler was 12.3 s, compared to the unfilled medical adhesive (clotting time 28.7 s), representing a 57.1% improvement in clotting efficiency, meeting the antibacterial and procoagulant performance requirements for implantable medical adhesives.

[0028] Example 2 A method for preparing implantable cyanoacrylate medical adhesive, comprising the following steps: (1) Low-temperature supercritical fluid gradient extraction: 100g of crude cyanoacrylate was placed in a supercritical extraction vessel, the extraction temperature was 32℃, and supercritical fluid was introduced. The pressure gradient was set to 8MPa→15MPa→25MPa, and the extraction times for each stage were 25min, 35min, and 45min, respectively. 0.5% medical ethanol was added as an entrainer.

[0029] (2) Molecular imprinted selective adsorption: The molecular imprinted polymer was prepared, eluted and verified using the same method as in Example 1. The preliminary purified solution was passed into a solid phase extraction column and the flow rate was controlled at 1.2 mL / min. The polymerization inhibitor was adsorbed and removed, and the polymer was eluted and regenerated for later use.

[0030] (3) Membrane separation and purification: The product is directly filtered and extracted using a modified polyethersulfone nanofiltration membrane with a molecular weight cutoff of 200 Da to remove macromolecular polymer impurities.

[0031] (4) Byproduct recovery and modification: The oligomer byproducts were collected and placed in a medical-grade sodium bicarbonate weak alkaline solution (pH 8.5-9.5) and hydrolyzed at 45°C for 2.5 h to prepare polycyanoacrylate nanoparticles; the nanoparticles were surface modified by succinic anhydride carboxyl modification method (similar to the amino modification process in Example 1, but the modifying reagent was adjusted to succinic anhydride) to obtain carboxyl-modified functional filler, which was then added back to high-purity medical adhesive at a ratio of 1 wt%; the medical adhesive was tested and found to have an inhibition zone diameter of 17.8 mm and a coagulation time of 13.1 s for Escherichia coli, and its antibacterial and procoagulant properties met the standards.

[0032] Comparative example (traditional distillation purification method) 100g of crude cyanoacrylate was purified using a conventional vacuum distillation process at a controlled temperature of 65℃, without selective adsorption or byproduct recovery steps.

[0033] The performance test results are shown in the table below: The results show that the medical adhesives prepared in Examples 1 and 2 of this invention have a purity far exceeding that of traditional processes, with extremely low levels of residual solvents and polymerization inhibitors. The low-temperature treatment throughout the process resulted in a monomer polymerization rate of less than 0.5%, fully meeting the stringent requirements for implantable medical materials. In contrast, traditional high-temperature distillation processes lead to severe monomer polymerization and excessive impurities, making them unsuitable for in vivo implantation. Furthermore, this invention achieves resource recycling and reduces production costs through byproduct recovery and modification, and is environmentally friendly with no harmful solvent residues.

[0034] Although the present invention has been disclosed above with reference to preferred embodiments, the embodiments are merely examples for illustrative purposes and are not intended to limit the present invention. Those skilled in the art can make various modifications and refinements without departing from the spirit and scope of the present invention. The scope of protection claimed by the present invention should be determined by the claims.

Claims

1. A method for preparing implantable cyanoacrylate medical adhesive, characterized in that, Includes the following steps: S1, Low-temperature supercritical Gradient extraction: Crude cyanoacrylate is added to a supercritical extraction vessel, sealed, and then purged with medical-grade cyanoacrylate. The extraction temperature was controlled below 40℃, and a multi-stage pressure gradient was set for stepwise extraction to remove impurities of different polarities step by step. The pre-purified solution was obtained by depressurization separation. S2. Selective adsorption purification: The preliminary purified solution obtained in step S1 is passed into a solid phase extraction column, and residual polymerization inhibitor impurities are removed by specific adsorption to obtain a purified solution. S3. Membrane separation and impurity removal: The purified solution obtained in step S2 is passed through a nanofiltration membrane to remove macromolecular polymer impurities and obtain high-purity cyanoacrylate monomer. S4. By-product resource utilization and modification: Collect the oligomer by-products generated during the extraction process in step S1, and prepare them into bioactive functional fillers through hydrolysis and surface modification. S5. Finished product preparation: The functional filler obtained in step S4 is re-mixed into the high-purity cyanoacrylate monomer obtained in step S3 in a certain proportion, and the mixture is mixed to obtain implantable cyanoacrylate medical adhesive.

2. The method for preparing an implantable cyanoacrylate medical adhesive according to claim 1, characterized in that, Step S1 specifically includes: S11, Low-pressure extraction: Control the extraction pressure to 8MPa and extract for 25-30min to remove unreacted monomers and other low-polarity impurities from the crude product; S12, Medium-pressure extraction: Increase the pressure to 15MPa and extract for 35-40 minutes. At the same time, add 0.5% by volume of medical ethanol as an entrainer to remove water and polar impurities such as organic acids. S13, High-pressure recovery: Increase the pressure to 25MPa, extract for 45-50min, recover the high-purity cyanoacrylate component, and obtain the preliminary purified solution.

3. The method for preparing an implantable cyanoacrylate medical adhesive according to claim 1, characterized in that, In step S2, the solid-phase extraction column is filled with a molecularly imprinted polymer, which is prepared by polymerization using hydroquinone as a template molecule and methacrylic acid as a functional monomer. The flow rate of the purification solution is controlled at 0.8-1.2 mL / min, and the hydroquinone polymerization inhibitor is specifically adsorbed and removed. After elution, the residual polymerization inhibitor is less than 0.1 ppm.

4. The method for preparing an implantable cyanoacrylate medical adhesive according to claim 1, characterized in that, In step S3, the nanofiltration membrane is a modified polyethersulfone nanofiltration membrane with a molecular weight cutoff of 200 Da. Filtration is performed at room temperature and pressure to completely remove macromolecular polymer impurities in the system while retaining small molecule cyanoacrylate monomers.

5. The method for preparing an implantable cyanoacrylate medical adhesive according to claim 1, characterized in that, Step S4 specifically includes: S41. The collected oligomer byproducts are placed in a weakly alkaline solution and hydrolyzed at a constant temperature for 2-3 hours to obtain polycyanoacrylate nanoparticles. S42. The nanoparticles are modified with amino or carboxyl groups to obtain antibacterial and procoagulant functional fillers with a particle size of 50-100 nm.

6. The method for preparing an implantable cyanoacrylate medical adhesive according to claim 1, characterized in that, In step S5, the re-addition of functional filler has a mass ratio of 0.1-1 wt%.

7. The method for preparing an implantable cyanoacrylate medical adhesive according to claim 2, characterized in that, After extraction and separation in step S1, the cyanoacrylate obtained has a purity of not less than 99.99% and a residual solvent content of less than 10 ppm.

8. The method for preparing an implantable cyanoacrylate medical adhesive according to claim 3, characterized in that, The molecularly imprinted polymer is regenerated by elution with a methanol / water mixture and can be reused.

9. The application of a method for preparing implantable cyanoacrylate medical adhesive as described in any one of claims 1-8, characterized in that, It is used in the preparation of cyanoacrylate medical adhesives for implantable surgical adhesions, intravenous wound hemostasis, or soft tissue repair.

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