α-cyanoacrylate medical adhesive with antibacterial properties and preparation method thereof

Abstract

The present invention provides an α-cyanoacrylate medical adhesive with antibacterial properties and a preparation method thereof. The provided α-cyanoacrylate medical adhesive with antibacterial properties includes a main component, a stabilizer, an extender, and an antibacterial agent. The main components are α-cyanoacrylate and methacrylate cyclopentane sulfone, which are used as a mixed medical adhesive matrix to obtain good bonding properties and good mechanical properties; at the same time, by adding hydroquinone as a stabilizer, the storage stability of the medical adhesive can be improved; at the same time, by adding an extender to squeeze out tissue fluid or blood on the tissue surface, the medical adhesive quickly generates chemical bonds with anions on the tissue surface to form a strong tissue adhesion force, so that the medical adhesive is quickly solidified into a film as a whole, and the polymerization heat is effectively reduced, thereby obtaining good blood drainage, hemostasis, tissue adhesion performance and good biocompatibility; at the same time, an antibacterial agent is added to obtain good antibacterial properties.

Description

Technical Field

[0001] The invention relates to the technical field of medical adhesives, and in particular to an alpha-cyanoacrylate medical adhesive with antibacterial properties and a preparation method thereof. Background Art

[0002] Medical adhesives are special functional adhesives for biomedicine. They are currently the preferred materials for medical surgery because of their advantages of easy use and short operation time. In addition to the usual bonding and mechanical functions, medical adhesives should also have biomedical functions. As biomedical engineering materials used to make contact with the human physiological environment, such as human tissue and blood, they are widely used in many aspects.

[0003] Currently, the commonly used medical adhesives on the market are usually composed of active ingredients and crosslinking agents. When used, the active ingredients and crosslinking agents need to be mixed through a blending injection head and then injected into the bleeding site. During clinical use, there is a disadvantage that the curing speed is uncontrollable, which can easily lead to unsatisfactory hemostasis effects. Cyanoacrylate medical adhesives have been rapidly developed and widely used in clinical applications in recent decades due to their excellent tissue bonding properties, good biocompatibility and degradability.

[0004] The monomer component of α-cyanoacrylate medical adhesive products is α-cyanoacrylate, CH2=C(CN)-COOR; after curing, polycyanoacrylate is formed, and the structural formula and reaction formula are as follows:

[0005]

[0006] Wherein R refers to -(CH2)3-CH3, -(CH2)7-CH3 and other substituents. The carbon atom position in the monomer is connected to polar groups -CN and -COOR. Such groups produce an inductive effect, making the carbon atom at the β-position have strong electron-absorbing properties. When encountering weak nucleophilic substances such as water, amino group, hydroxyl group, weak base, etc., anionic polymerization will rapidly occur, which will reduce the double bond electron cloud density and form multipolar centers in the polymer. The instantaneous polymerization reaction will instantly turn the liquid adhesive into a solid adhesive medium, so that tissues or tissues and materials can be bonded together.

[0007] At present, cyanoacrylate medical adhesives have been used in clinical practice for a long time. The main application areas include: bonding of incisions and wounds on the body surface, sealing and stopping bleeding of organ sections in the body, and embolization of esophageal varicose veins. Cyanoacrylate medical adhesives have the advantages of single component, simple and easy to use, rapid curing at room temperature, and high bonding strength. However, this type of medical adhesive also has disadvantages such as high film hardness, high brittleness, insufficient porosity, and easy inflammatory reaction of tissues, which limits its further wide application. Summary of the invention

[0008] In view of this, the present invention provides an α-cyanoacrylate medical adhesive with antibacterial properties and a preparation method thereof to solve the above problems.

[0009] The technical solution of the present invention is achieved in this way:

[0010] A method for preparing an α-cyanoacrylate medical adhesive having antibacterial properties comprises the following steps:

[0011] S1. Fill an inert gas into a dry sealed container to exclude air, add the main component of α-cyanoacrylate to the container, add a stabilizer, hydroquinone and an extender, stir and mix to obtain a mixed solution;

[0012] S2. The main component of methacrylate sulfolane ester is added to the mixture, and stirring is continued until the methacrylate sulfolane ester is completely dissolved;

[0013] S3. Add an antibacterial agent, stir until completely dissolved, and then sterilize to obtain an α-cyanoacrylate medical adhesive with antibacterial properties.

[0014] Furthermore, the α-cyanoacrylate in S1 is one of ethyl α-cyanoacrylate, n-butyl α-cyanoacrylate, isobutyl α-cyanoacrylate, and n-octyl α-cyanoacrylate, preferably n-butyl α-cyanoacrylate or n-octyl α-cyanoacrylate.

[0015] Furthermore, the amount of α-cyanoacrylate added in S1 accounts for 80-97% of the total weight of the main components, preferably 88-95%.

[0016] Furthermore, the amount of stabilizer added in S1 is 0.004-0.006% of the total weight of the main components, preferably 0.005%.

[0017] Furthermore, the extender in S1 is one of p-toluenesulfonic acid, formic acid, acetic acid, citric acid, lactic acid, and butyric acid, preferably acetic acid or formic acid.

[0018] Furthermore, the amount of the extender added is 0.005-0.5%, preferably 0.1-0.3%, of the total weight of the main components.

[0019] Furthermore, the inert gas in S1 is one of nitrogen, argon and helium, preferably nitrogen.

[0020] Furthermore, the amount of sulfolane methacrylate added to S2 accounts for 3-20% of the total weight, preferably 5-12%.

[0021] Furthermore, the antibacterial agent in S3 is one of ciprofloxacin, triclosan and chlorhexidine, preferably triclosan.

[0022] Furthermore, the amount of antibacterial agent added is 0.01-5%, preferably 0.1-1%, based on the total weight of the main components.

[0023] Furthermore, the method for preparing the α-cyanoacrylate medical adhesive having antibacterial properties prepares an α-cyanoacrylate medical adhesive having antibacterial properties.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows: the α-cyanoacrylate medical adhesive with antibacterial properties of the present invention mainly comprises α-cyanoacrylate and cyclopentane methacrylate, which are used as a mixed medical adhesive matrix to obtain good bonding properties and good mechanical properties; at the same time, by adding hydroquinone as a stabilizer, the storage stability of the medical adhesive can be improved; at the same time, by adding an extender to squeeze out tissue fluid or blood on the tissue surface, the medical adhesive quickly generates chemical bonds with anions on the tissue surface to form a strong tissue adhesion force, so that the medical adhesive is quickly solidified into a film as a whole, and the polymerization heat is effectively reduced, thereby obtaining good blood drainage, hemostasis, tissue adhesion and good biocompatibility; at the same time, by adding an antibacterial agent, good antibacterial properties can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a diagram showing the curing film expansion of the α-cyanoacrylate medical adhesive with antibacterial properties in Example 1;

[0026] Figure 2 These are the antibacterial effect diagrams of the α-cyanoacrylate medical adhesive with antibacterial properties of Example 1. The left diagram is the antibacterial effect diagram for Escherichia coli, and the right diagram is the antibacterial effect diagram for Staphylococcus aureus. DETAILED DESCRIPTION

[0027] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0028] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0029] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0030] Example 1

[0031] A method for preparing an α-cyanoacrylate medical adhesive having antibacterial properties comprises the following steps:

[0032] S1. Fill a dry sealed container with nitrogen to remove air, weigh 9g of the main ingredient α-cyanoacrylate n-butyl ester and add it to the container, then add 0.0005g of hydroquinone and 0.01g of an extender, wherein the extender is acetic acid, stir and mix to obtain a mixed solution.

[0033] S2. Add 1 g of cyclopentane methacrylate, one of the main components, into the above mixture and continue stirring for 30 min until the cyclopentane methacrylate is completely dissolved.

[0034] S3. Add 0.01 g of an antibacterial agent, such as triclosan, and stir for 30 minutes until it is completely dissolved, and then sterilize to obtain an α-cyanoacrylate medical adhesive with antibacterial properties.

[0035] Example 2

[0036] Compared with Example 1, the difference between this example is that the amount of n-butyl α-cyanoacrylate added in the main component of step S1 is 9.5 g, and the amount of cyclopentane methacrylate added in the main component of step S2 is 0.5 g.

[0037] Example 3

[0038] Compared with Example 1, the difference between this example is that the amount of n-butyl α-cyanoacrylate added in the main component of step S1 is 8.8 g, and the amount of cyclopentane methacrylate added in the main component of step S2 is 1.2 g.

[0039] Example 4

[0040] The present embodiment is different from the embodiment 1 in that the amount of α-octyl cyanoacrylate added as the main component in step S1 is 9 g, and the amount of cyclopentane methacrylate added as the main component in step S2 is 1 g.

[0041] Example 5

[0042] The present embodiment is different from the embodiment 1 in that the extender in step S1 is formic acid, and the added amount is 0.01 g.

[0043] Example 6

[0044] The difference between this embodiment and embodiment 1 is that the amount of the extender added in step S1 is 0.05 g.

[0045] Example 7

[0046] The difference between this embodiment and embodiment 1 is that the amount of antibacterial agent added in step S3 is 0.0001 g.

[0047] Example 8

[0048] Compared with Example 1, the difference between this example and Example 1 is that in step S3, the antibacterial agent is ciprofloxacin, and the added amount is 0.01 g.

[0049] Comparative Example 1

[0050] Compared with Example 1, the difference between this comparative example and Example 1 is that the method for preparing the α-cyanoacrylate medical adhesive with antibacterial properties comprises the following steps:

[0051] First, nitrogen is filled into a dry sealed container to remove air, 10 g of n-butyl α-cyanoacrylate is weighed and added into the container, and then 0.0005 g of hydroquinone is added, stirred and mixed, and then sterilized to obtain an α-cyanoacrylate medical adhesive with antibacterial properties.

[0052] 1. Polymerization performance test

[0053] In a culture dish with a diameter of 90 mm, 50 mL of a sodium bicarbonate solution with a mass concentration of 0.3 g / L was added, and one drop of each of the medical adhesives of Examples 1-7 and Comparative Example 1 was taken with a dropper at a height of 5 cm. The curing time and the diameter of the medical adhesives prepared in Examples 1-7 and Comparative Example 1 were observed, respectively. The diameter of the film reflects the performance of the medical adhesive in expelling blood or tissue fluid. The test was performed 5 times, and the average value was taken as the test result. The test results are shown in Table 1.

[0054] Table 1 Polymerization properties of medical adhesives

[0055] serial number Curing film forming time / s Diameter of membrane / cm Example 1 20.7 4.0 Example 2 19.4 3.9 Example 3 22.4 4.1 Example 4 21.6 4.4 Example 5 19.9 3.8 Example 6 24.1 4.4 Example 7 19.25 4.1 Comparative Example 1 15.8 1.2

[0056] From the data comparison of Examples 1-7 and Comparative Example 1 in Table 1, it can be seen that the present application scheme adds methacrylate cyclopentane sulfonate, an extender and an antibacterial agent. Although the curing film-forming time of the medical adhesive with the above-mentioned components is increased, it can still meet the needs of clinical operation, and the diameter of the film with the above-mentioned components is significantly increased. The increase in the film-forming diameter means that the contact area between the medical adhesive and the wound surface increases, which helps the adhesive to more effectively expel the blood or tissue fluid on the wound surface and ensure the close contact between the adhesive and the wound surface. Close contact is the basis for the medical adhesive to play an adhesive role, and it is also the key to achieve effective hemostasis and promote wound healing. The present invention application forms a polymer network by adding methacrylate cyclopentane sulfonate, methacrylate cyclopentane sulfonate and α-cyanoacrylate. The introduction of methacrylate cyclopentane sulfonate changes the structure of the polymer network, making the network more loose and open, thereby increasing the porosity. At the same time, this loose network structure is conducive to the flow and diffusion of the medical adhesive, so that a larger film-forming diameter can be formed when applied or applied. By adding an extender, the viscosity of the medical adhesive can be effectively reduced, so that the medical adhesive is easier to flow and spread when applied or applied, so that a larger film-forming diameter can be formed. The extender can also enhance the wetting properties of the medical adhesive, making it easier to wet and spread on the wound surface or other adherend surfaces. The improvement of this wetting and diffusion properties helps the adhesive to better contact the adherend surface and squeeze out the blood or tissue fluid on the wound surface. The reduction in viscosity and the improvement of wetting properties act together on the film-forming process of the adhesive, making the formed film more uniform and smooth. This uniform film structure helps to improve the adhesion of the adhesive and the performance of squeezing out blood or tissue fluid. From the results of Example 1 compared with Example 6 in Table 1, it can be seen that the increase in the amount of extender will increase the diameter and ductility of the film, further improve the performance of squeezing out blood or tissue fluid, but will also lead to the extension of the curing time. Therefore, the amount of extender used under a specific ratio is required to be able to take into account the performance of squeezing out blood or tissue fluid during the curing time.

[0057] The curing film formation of the medical adhesive in Example 1 of the present invention is as follows Figure 1 shown.

[0058] 2. Mechanical properties test

[0059] In a culture dish with a diameter of 90 mm, 50 mL of a sodium bicarbonate solution with a mass concentration of 0.3 g / L was added, and 0.5 g of the medical adhesives of Examples 1-3, Example 7 and Comparative Example 1 were respectively taken with a dropper and dropped at a height of 5 cm to solidify the medical adhesives into films. The hardness and brittleness of the medical adhesives prepared in Examples 1-3, Example 7 and Comparative Example 1 after curing into films were tested using a texture analyzer in TPA mode, and the tests were performed 3 times respectively, and the average values ​​were taken as the test results. The test results are shown in Table 2.

[0060] Table 2 Mechanical properties of medical adhesives

[0061]

[0062]

[0063] From the data comparison of Examples 1-3, Example 7 and Comparative Example 1 in Table 2, it can be seen that the hardness and brittleness of Examples 1-3 and Example 7 are all less than Comparative Example 7. It can be seen that with the introduction of methacrylic acid sulfolane ester, the hardness and brittleness of the medical adhesive after curing film are significantly improved, proving that methacrylic acid sulfolane ester can effectively improve the mechanical properties of medical adhesives, effectively avoid the defects of cyanoacrylate medical adhesive films such as high hardness and large brittleness, and are more suitable for clinical applications. This is because methacrylic acid sulfolane ester contains a special sulfolane group in its molecular structure. This group can introduce a flexible segment in the polymerization reaction, thereby changing the overall structure of the polymer. The introduction of a flexible segment can increase the mobility of the polymer chain, making it easier for the polymer to form a relatively loose network structure during the curing process, rather than a tightly packed hard structure. Therefore, the adhesive cured film finally obtained has a lower hardness and better toughness, that is, the brittleness is effectively reduced. This improvement enables the adhesive to better adapt to the shape and change of the bonded surface, thereby improving the bonding effect and durability. At the same time, by comparing the data of Example 1 and Example 7, it can be seen that the amount of antibacterial agent introduced does not affect the mechanical properties of the product.

[0064] 3. Adhesion performance test

[0065] The wound closure strength of the medical adhesives prepared in Examples 1-3, Examples 7-8 and Comparative Example 1 was tested respectively according to the method of YY / T 0729.4-2009 "Test Method for Adhesive Properties of Tissue Adhesives Part 4: Wound Closure Strength". The tests were performed three times respectively and the average values ​​were taken as the test results. The test results are shown in Table 3.

[0066] Table 3 Adhesive properties of medical adhesives

[0067] serial number Bonding length / cm Bonding width / cm Wound closure strength / N Example 1 2.5 1.0 51.662 Example 2 2.5 1.0 52.252 Example 3 2.5 1.0 59.728 Example 7 2.5 1.0 51.245 Comparative Example 1 2.5 1.0 38.481

[0068] From the data of Examples 1-3 and Example 7 in Table 3, it can be seen that the introduction of the antibacterial agent does not affect the bonding length and bonding width of the product. At the same time, from the data of Examples 1-3 and Example 7 in Table 3, it can be seen that the wound closure strength of the medical adhesive is greatly improved by adding methacrylate sulfolane and an extender, and it can have good tissue adhesion performance, wound closure performance and hemostasis performance, which is more suitable for clinical application. This is because the addition of methacrylate sulfolane changes the network structure of the polymer. As a comonomer, it copolymerizes with α-cyanoacrylate and introduces different chemical groups and segments. This change makes the polymer network more uniform and dense, thereby improving the mechanical strength and adhesion of the adhesive. The molecular structure of methacrylate sulfolane contains sulfolane groups, which have strong intermolecular forces. In the polymer network, these groups can form stronger interactions with other molecular segments, thereby improving the cohesion and adhesion of the adhesive. In addition, the addition of methacrylate cyclopentane sulfone ester also makes the polymer network have better flexibility and impact resistance. This performance improvement helps the adaptability and stability of the adhesive in a complex wound environment, and improves the strength and effect of wound closure. At the same time, the addition of an extender can reduce the viscosity of the adhesive, making it easier to apply and penetrate. The reduction in viscosity helps the adhesive to better contact the wound surface and form a tighter adhesion layer. The extender can also enhance the wetting properties of the adhesive, making it easier to diffuse and penetrate on the wound surface. This performance improvement helps the adhesive to better fill the wound gap and improve the wound closure performance. By reducing viscosity and promoting wetting, the extender indirectly enhances the adhesion properties of the adhesive. This allows the adhesive to better combine with the wound tissue and form a more solid adhesion layer, thereby improving the strength and stability of wound closure.

[0069] 4. Antibacterial performance test

[0070] The antibacterial effects of the medical adhesives prepared in Example 1, Examples 7-8 and Comparative Example 1 were tested according to the method of GB 15979-2002 "Hygiene Standards for Disposable Hygiene Products". The medical adhesives prepared in Example 1, Examples 7-8 and Comparative Example 1 were sprayed on the center of the culture dish, and placed in a constant temperature box for culture. After the culture was completed, the antibacterial ring was observed.

[0071] After the culture is finished, an obvious antibacterial ring can be observed at the center of the culture dish sprayed with the medical adhesive of the present invention. It is confirmed by observation that the present invention has different degrees of antibacterial properties for Staphylococcus aureus and Escherichia coli by adding antibacterial agents, whether triclosan, ciprofloxacin or chlorhexidine, and the antibacterial properties are significantly improved as the amount added increases. Therefore, the present invention can effectively inhibit the occurrence of tissue inflammation by adding antibacterial agents.

[0072] The test results of Example 1 of the present invention are as follows Figure 2 shown.

[0073] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing an α-cyanoacrylate medical adhesive having antibacterial properties, characterized in that: The following steps are involved: S1. Fill an inert gas into a dry sealed container to exclude air, add the main component of α-cyanoacrylate to the container, add a stabilizer, hydroquinone and an extender, stir and mix to obtain a mixed solution; S2. The main component of methacrylate sulfolane ester is added to the mixture, and stirring is continued until the methacrylate sulfolane ester is completely dissolved; S3. Add an antibacterial agent, stir until completely dissolved, and then sterilize to obtain an α-cyanoacrylate medical adhesive with antibacterial properties.

2. The method for preparing an α-cyanoacrylate medical adhesive having antibacterial properties as claimed in claim 1, characterized in that: The α-cyanoacrylate in S1 is one of ethyl α-cyanoacrylate, n-butyl α-cyanoacrylate, isobutyl α-cyanoacrylate, and n-octyl α-cyanoacrylate.

3. The method for preparing an α-cyanoacrylate medical adhesive with antibacterial properties as claimed in claim 1 or 2, characterized in that: The amount of α-cyanoacrylate added in S1 accounts for 80-97% of the total weight of the main components, and the amount of stabilizer added in S1 accounts for 0.004-0.006% of the total weight of the main components.

4. The method for preparing an α-cyanoacrylate medical adhesive having antibacterial properties as claimed in claim 1, characterized in that: The extender in S1 is one of p-toluenesulfonic acid, formic acid, acetic acid, citric acid, lactic acid and butyric acid.

5. The method for preparing an α-cyanoacrylate medical adhesive having antibacterial properties as claimed in claim 4, characterized in that: The amount of the extender added is 0.005-0.5% of the total weight of the main components.

6. The method for preparing an α-cyanoacrylate medical adhesive having antibacterial properties as claimed in claim 1, characterized in that: The inert gas in S1 is one of nitrogen, argon and helium.

7. The method for preparing an α-cyanoacrylate medical adhesive having antibacterial properties as claimed in claim 1, characterized in that: The amount of sulfolane methacrylate added to S2 accounts for 3-20% of the total weight of the main components.

8. The method for preparing an α-cyanoacrylate medical adhesive with antibacterial properties as claimed in claim 1, characterized in that: The antibacterial agent in S3 is one of ciprofloxacin, triclosan and chlorhexidine.

9. The method for preparing an α-cyanoacrylate medical adhesive having antibacterial properties as claimed in claim 8, characterized in that: The amount of the antibacterial agent added is 0.01-5% of the total weight of the main components.

10. An α-cyanoacrylate medical adhesive with antibacterial properties prepared by the method for preparing an α-cyanoacrylate medical adhesive with antibacterial properties as claimed in any one of claims 1 to 9.

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