Medical tissue adhesive and preparation method thereof

Abstract

The present application relates to the technical field of adhesives, and in particular to a medical tissue adhesive and a preparation method thereof. The medical tissue adhesive comprises the following raw materials in parts by weight: 8-12 parts of a polyglutamic acid grafted thermosensitive polymer, 0.8-1.2 parts of vitamin C, 0.8-1.2 parts of sodium periodate, 0-1.2 parts of sodium alginate, 0-1.2 parts of chitosan oligosaccharide, and 2.5-3.5 parts of polyethylene glycol; the polyglutamic acid grafted thermosensitive polymer is prepared by reacting polyglutamic acid and a thermosensitive polymer containing an acid anhydride, and the temperature-sensitive polymer is prepared by copolymerizing an acid anhydride containing a double bond, N-vinyl pyrrolidone, and N-isopropylacrylamide; the medical tissue adhesive has the advantages of improving the hemostatic effect and adhesion of the medical adhesive.

Description

Technical Field

[0001] The present application relates to the technical field of adhesives, and in particular to a medical tissue adhesive and a preparation method thereof. Background Art

[0002] Medical adhesives primarily include tissue adhesives, hemostats, and tissue sealants, and are widely used in clinical surgery. Tissue adhesives can be broadly defined as any substance with in situ polymerization properties that allows tissue to adhere to other tissues or to non-tissue surfaces, controlling bleeding (e.g., hemostats) or acting as a barrier to gas and liquid leakage (e.g., sealants). Ideal biomedical adhesives are expected to simultaneously meet requirements such as biocompatibility, biodegradability, mechanical conformability with underlying tissues, an acceptable swelling index, and storage stability. Furthermore, they must be safe, non-toxic, easy to sterilize, prepare, and store.

[0003] Currently, commonly used medical adhesives on the market typically package the active ingredient and crosslinker separately. These are dissolved separately to create a solution, then mixed using a blending injector tip and injected into the bleeding site. Besides being inconvenient during clinical use, these adhesives also lack adhesion and easily separate from the wound, resulting in poor hemostatic effects. Summary of the Invention

[0004] In order to improve the hemostatic effect and bonding strength of medical adhesives, the present application provides a medical tissue adhesive and a preparation method thereof.

[0005] In a first aspect, the present application provides a medical tissue adhesive, which adopts the following technical solution:

[0006] A medical tissue adhesive comprises the following raw materials in parts by weight: 8-12 parts of a polyglutamic acid grafted thermosensitive polymer, 0.8-1.2 parts of vitamin C, 0.8-1.2 parts of sodium periodate, 0-1.2 parts of sodium alginate, 0-1.2 parts of chitosan oligosaccharide, and 2.5-3.5 parts of polyethylene glycol;

[0007] The polyglutamic acid grafted thermosensitive polymer is prepared by reacting polyglutamic acid and a thermosensitive polymer containing anhydride, and the thermosensitive polymer is prepared by copolymerizing anhydride containing a double bond, N-vinyl pyrrolidone and N-isopropylacrylamide.

[0008] By adopting the above technical solution, a thermosensitive polymer is prepared and an anhydride structure is introduced into the thermosensitive polymer, enabling the thermosensitive polymer to bond with polyglutamic acid in an alkaline environment through the anhydride structure. Due to the presence of a large number of hydrophilic groups such as amide groups and carbonyl groups in the thermosensitive polymer, the water absorption of the medical tissue adhesive is enhanced, which can shorten the tissue adhesion time. Moreover, the thermosensitive polymer shrinks in volume as the temperature rises after being placed close to the skin. This shrinkage can squeeze wounds and damaged capillaries, thereby improving the hemostatic effect. The N-vinyl pyrrolidone introduced into the thermosensitive polymer has excellent biocompatibility, making the medical tissue adhesive more adhesive. The added sodium alginate and chitosan oligosaccharide are both highly water-soluble and can quickly absorb water, promoting the gelation of the adhesive. Both sodium alginate and chitosan oligosaccharide can also play a role in thickening and film-forming, making the overall gelation of the adhesive stronger and increasing its hydrogen bond content, thereby increasing tissue peeling force.

[0009] Preferably, the preparation method of the temperature-sensitive polymer is as follows:

[0010] A mixture of 80-120 parts by weight of an acid anhydride containing a double bond, N-vinyl pyrrolidone, and N-isopropylacrylamide is added to a solvent in a molar ratio of 1:(2-6):(33-37). The mixture is stirred until dissolved. A free radical initiator is then added at a molar ratio of 0.02% of the total monomer amount. The mixture is heated to 60-70°C under a nitrogen atmosphere and stirred for reaction to obtain a temperature-sensitive polymer.

[0011] By adopting the above technical solution and preparing by free radical polymerization, the polymerization process can be carried out more smoothly and the progress of the reaction can be better controlled.

[0012] Preferably, the acid anhydride containing a double bond is one or more of maleic anhydride, methacrylic anhydride and citraconic anhydride.

[0013] Preferably, the free radical initiator is azobisisobutyronitrile or azobisisoheptanenitrile.

[0014] By adopting the above technical solution, both free radical initiators can stably and efficiently generate free radicals to initiate free radical polymerization.

[0015] Preferably, the preparation method of the polyglutamic acid grafted thermosensitive polymer is as follows:

[0016] The polyglutamic acid is dissolved in deionized water, and then the thermosensitive polymer is added. The mass ratio of polyglutamic acid to the thermosensitive polymer is (1.8-2.2):1. The mixture is stirred until dissolved. The pH is adjusted to 8-9. The mixture is stirred for 5-8 hours. The mixture is dialyzed and freeze-dried to obtain the polyglutamic acid-grafted thermosensitive polymer.

[0017] By adopting the above technical solution, taking into account the reactive groups and the steric hindrance effect of the reaction, and controlling the mass ratio of the thermosensitive polymer and polyglutamic acid, the reaction time and the solution pH, the two can be fully grafted.

[0018] Preferably, the added weight portion of sodium alginate is 1 part, and the added weight portion of chitosan oligosaccharide is 1 part.

[0019] By adopting the above technical solution, sodium alginate and chitosan oligosaccharide are both highly water-soluble, capable of rapidly absorbing water and promoting the gelation of the adhesive. Furthermore, both sodium alginate and chitosan oligosaccharide can play a role in thickening and film-forming, making the overall gelation of the adhesive stronger, and can also increase its hydrogen bond content, thereby enhancing tissue peeling force. The two have a synergistic effect on the gelation time and strength of the adhesive. By controlling the addition ratio of the two, the performance of the adhesive can be optimized.

[0020] Preferably, the medical tissue adhesive further comprises 0.08-0.12 parts by weight of alkyl glycoside.

[0021] By adopting the above technical solution, the alkyl polyglycoside has a certain foaming effect and is relatively safe. It can exert its foaming effect after the adhesive absorbs water to form a gel, causing the adhesive to further expand in volume, exerting a squeezing effect on the wound, thereby enhancing the hemostatic effect. By squeezing the wound surface, the tissue peeling force is also improved.

[0022] In a second aspect, the present application provides a method for preparing a medical tissue adhesive, which adopts the following technical solution:

[0023] A method for preparing a medical tissue adhesive comprises the following steps:

[0024] The raw materials are mixed in proportion, dried at 48-53° C., and then continued to be mixed evenly at this temperature. After cooling, the sample is ground into powder to obtain a medical tissue adhesive.

[0025] By adopting the above technical solution, there are no technical difficulties in the preparation process of the adhesive of the present application. It is only necessary to control the temperature and drying conditions. The obtained adhesive has a high qualified rate and uniform quality and is suitable for mass production.

[0026] In summary, this application includes at least one of the following beneficial technical effects:

[0027] 1. By preparing a thermosensitive polymer and introducing an anhydride structure into the thermosensitive polymer, the thermosensitive polymer can bond with polyglutamic acid in an alkaline environment through the anhydride structure. Due to the high concentration of hydrophilic groups such as amide and carbonyl groups in the thermosensitive polymer, the water absorption of the medical tissue adhesive is enhanced, shortening the tissue adhesion time. Furthermore, the thermosensitive polymer shrinks in volume as the temperature rises when placed against the skin. This contraction squeezes wounds and damaged capillaries, thereby improving hemostasis. The N-vinylpyrrolidone introduced into the thermosensitive polymer has excellent biocompatibility, further enhancing the adhesive's adhesion. The added sodium alginate and chitosan oligosaccharides are both highly water-soluble, enabling rapid water absorption and promoting gelation of the adhesive. Both sodium alginate and chitosan oligosaccharides act as thickeners and film-forming agents, enhancing the adhesive's overall gelation properties and increasing its hydrogen bonding content, resulting in greater tissue peeling force.

[0028] 2. The medical tissue adhesive prepared in this application can achieve good adhesion within 20 seconds, and the tissue peeling force at 10 minutes is between 376.2-412.3 g / cm; this shows that the medical tissue adhesive prepared in this application can adhere to the wound in a short time, has a good hemostatic effect, and has a high bonding force, is not easy to detach from the wound, and can allow the wound sufficient healing time. DETAILED DESCRIPTION

[0029] The following is a further detailed description of this application in conjunction with the specific content.

[0030] raw material

[0031] The raw materials used in this application were all purchased from the market, among which the average molecular weight of polyglutamic acid is 200,000; sodium alginate is food grade, mesh size is 80 mesh, CAS number is 9005-38-3, and the manufacturer is Anhui Weimao Biotechnology Co., Ltd.; chitosan oligosaccharide is food grade, and the manufacturer is Qingdao Chengrunda Food Ingredients Co., Ltd.; the average molecular weight of polyethylene glycol is 1500; and the alkyl glycoside is APG0810. Example

[0032] Example 1

[0033] A medical tissue adhesive, the preparation method of which is as follows:

[0034] S1. Preparation of a thermosensitive polymer: 100 g of a monomer was added to 450 g of tetrahydrofuran, wherein the monomers were a mixture of maleic anhydride, N-vinyl pyrrolidone, and N-isopropylacrylamide in a molar ratio of 1:4:35. After stirring until dissolved, 0.02% of the total molar amount of azobisisobutyronitrile was added, and the temperature was raised to 65° C. and stirred under a nitrogen atmosphere for 12 h. The solvent was then removed by rotary evaporation to obtain a thermosensitive polymer, i.e., a copolymer of maleic anhydride, N-vinyl pyrrolidone, and N-isopropylacrylamide. Testing showed that the number average molecular weight (Mn) of the copolymer was 4W, and the molecular weight distribution was 1.43.

[0035] S2. Preparing a polyglutamic acid-grafted thermosensitive polymer: dissolving polyglutamic acid in deionized water, and then adding the thermosensitive polymer. The mass ratio of polyglutamic acid to the thermosensitive polymer is 2:1. The amount of water is just enough to dissolve the polyglutamic acid and the thermosensitive polymer. The pH is adjusted to 9, and the reaction is stirred for 6 hours. The mixture is dialyzed and freeze-dried to obtain a polyglutamic acid-grafted thermosensitive polymer. The number average molecular weight (Mn) of the polymer is 28.1W, and the molecular weight distribution is 1.37.

[0036] S3. Mix polyglutamic acid grafted thermosensitive polymer, vitamin C, sodium periodate, sodium alginate, chitosan oligosaccharide and polyethylene glycol in a mass ratio of 10:1:1:1:1:3, then dry at 50°C, and continue to mix evenly at this temperature. After cooling, grind the sample into powder to obtain a medical tissue adhesive.

[0037] Example 2

[0038] A medical tissue adhesive is different from Example 1 in that the molar ratio of maleic anhydride, N-vinyl pyrrolidone and N-isopropylacrylamide is 1:2:37, and the remaining steps are the same as Example 1.

[0039] Example 3

[0040] A medical tissue adhesive is different from Example 1 in that the molar ratio of maleic anhydride, N-vinyl pyrrolidone and N-isopropylacrylamide is 1:6:33, and the remaining steps are the same as Example 1.

[0041] Example 4

[0042] A medical tissue adhesive is different from Example 1 in that sodium alginate is not added to the raw materials, and the remaining steps are the same as Example 1.

[0043] Example 5

[0044] A medical tissue adhesive is different from Example 1 in that chitosan oligosaccharide is not added to the raw materials, and the remaining steps are the same as those of Example 1.

[0045] Example 6

[0046] A medical tissue adhesive glue differs from Example 1 in that alkyl glycoside is further added to the raw materials, and the mass ratio of polyglutamic acid grafted thermosensitive polymer, vitamin C, sodium periodate, sodium alginate, chitosan oligosaccharide, polyethylene glycol and alkyl glycoside is 10:1:1:1:1:3:0.1. The remaining steps are the same as in Example 1.

[0047] Comparative Example

[0048] Comparative Example 1

[0049] A medical tissue adhesive is different from Example 1 in that sodium alginate and chitosan oligosaccharide are not added in S3, and the remaining steps are the same as those in Example 1.

[0050] Comparative Example 2

[0051] A medical tissue adhesive is provided, which differs from Example 1 in that the polyglutamic acid grafted thermosensitive polymer in the raw material is replaced by a mixture of equal masses of polyglutamic acid and the thermosensitive polymer, and the mass ratio of polyglutamic acid to the thermosensitive polymer is 2:1. The remaining steps are the same as those in Example 1.

[0052] Comparative Example 3

[0053] A medical tissue adhesive is different from Example 1 in that, during the preparation of the temperature-sensitive polymer in the raw material, N-vinyl pyrrolidone is replaced with an equimolar amount of N-isopropylacrylamide, and the remaining steps are the same as Example 1.

[0054] Performance testing

[0055] Detection method / test method

[0056] Medical tissue adhesives were prepared according to the preparation methods of Examples 1-6 and Comparative Examples 1-3, and then tested according to the following test methods. The test results are shown in Table 1.

[0057] Place medical tissue adhesive between two pieces of fresh pig skin, with the contact area of ​​the two pig skins being 2x2cm 2The amount of medical tissue adhesive used was 2cm x 2cm x 0.01cm, meaning the powdered medical tissue adhesive had a thickness of 0.01cm. Two pigskins were then clamped and immersed in saline to simulate contact with blood. The bonded pigskins were then lifted every 10 seconds and a 50g weight was suspended from one end. The tissue bonding time was determined by the time the two pieces of pigskin were completely bonded without sliding and could withstand the weight of the 50g weight. After 10 minutes of bonding, the samples were peeled at a 90° angle, and the tissue peeling force was tested using a tensile tester.

[0058] The hemostatic performance of the medical tissue adhesive was tested by a rat back skin hemostasis experiment. The backs of 9 healthy rats were scratched with a wound depth of 2 mm and a length of 1 cm, and the wounds were in a continuous bleeding state. Then, the medical tissue adhesives of Examples 1-6 and Comparative Examples 1-3 were placed on the wounds of the rats respectively, completely covering the wounds with a thickness of 1 mm, and then pressed for 20 seconds. After releasing, it was observed that the wounds on the backs of the rats corresponding to Examples 1-6 and Comparative Example 3 no longer oozed blood, and a gel-like adhesive that adhered to the wounds could be observed at the wounds. Comparative Example 1-2 was not completely bonded and still had a small amount of bleeding. This shows that the medical tissue adhesives of Examples 1-6 of the present application have good hemostatic effects. And after 10 minutes, the medical tissue adhesives of Examples 1-6 can be observed to have slight wrinkling on their adhesive surfaces. This is because the temperature-sensitive polymer shrinks in volume as the temperature rises after it is close to the skin. Through shrinkage, the wound and damaged capillaries can be squeezed, thereby achieving a better hemostatic effect.

[0059] Table 1 Test results of Examples 1-6 and Comparative Examples 1-3

[0060]

[0061] It can be seen from Examples 1-6 and Comparative Examples 1-3, as well as the test data in Table 1, that the medical tissue adhesive prepared in the present application can achieve good adhesion within 20 seconds, and the tissue peeling force at 10 minutes is between 376.2-412.3 g / cm; this indicates that the medical tissue adhesive prepared in the present application can adhere to the wound in a short time, has a good hemostatic effect, and has a high bonding force, is not easy to detach from the wound, and can allow the wound sufficient healing time.

[0062] By preparing a thermosensitive polymer and introducing an anhydride structure into the thermosensitive polymer, the thermosensitive polymer can bond with polyglutamic acid in an alkaline environment through the anhydride structure. This enhances the water absorption of the medical tissue adhesive and shortens the tissue adhesion time. Furthermore, the introduction of biocompatible N-vinyl pyrrolidone into the thermosensitive polymer further enhances the adhesiveness of the medical tissue adhesive. The test data from Example 1 and Comparative Example 3 demonstrate that, in conjunction with Examples 2-3, when the molar ratio of maleic anhydride, N-vinyl pyrrolidone, and hydroxyethyl methacrylate is 1:(2-6):(33-37), the resulting medical tissue adhesive maintains excellent tissue adhesion time and tissue peeling force. Furthermore, in conjunction with the test data from Comparative Example 2, if the thermosensitive polymer is directly mixed into the adhesive, it essentially bonds to the system only through hydrogen bonds, resulting in a reduced degree of crosslinking and a failure to effectively utilize its thermosensitive properties. Furthermore, the adhesive strength deteriorates, resulting in reduced tissue peeling force.

[0063] The sodium alginate and chitosan oligosaccharide added to the raw materials of the present application are both highly water-soluble and can rapidly absorb water, promoting the gelation of the adhesive. Furthermore, both sodium alginate and chitosan oligosaccharide can thicken and form films, making the overall gelation of the adhesive stronger, and can increase its hydrogen bond content, thereby increasing the tissue peeling force. The two have a synergistic effect on the gelation time and strength of the adhesive, as can be seen from the test data of Example 1, Examples 4-5, and Comparative Example 1.

[0064] Furthermore, by adding a certain amount of alkyl glycoside to the adhesive, the alkyl glycoside has a certain foaming effect and is relatively safe. After the adhesive absorbs water and forms a gel, the alkyl glycoside can exert its foaming effect, further expanding the volume of the adhesive, exerting a squeezing effect on the wound, thereby enhancing the hemostatic effect. Furthermore, by squeezing the wound surface, the tissue peeling force is also improved. This is verified by the test data of Examples 1 and 6.

[0065] This specific embodiment is merely an explanation of the present invention and is not intended to limit the present invention. After reading this specification, those skilled in the art may make non-creative modifications to this embodiment as needed. However, as long as such modifications are within the scope of the claims of the present invention, they are protected by patent law.

Claims

1. A medical tissue adhesive, characterized in that: The method comprises the following raw materials in parts by weight: 8-12 parts of polyglutamic acid grafted thermosensitive polymer, 0.8-1.2 parts of vitamin C, 0.8-1.2 parts of sodium periodate, 0-1.2 parts of sodium alginate, 0-1.2 parts of chitosan oligosaccharide, 2.5-3.5 parts of polyethylene glycol and 0.08-0.12 parts of alkyl glycoside; The polyglutamic acid grafted thermosensitive polymer is prepared by reacting polyglutamic acid and a thermosensitive polymer containing anhydride, and the thermosensitive polymer is prepared by copolymerizing anhydride containing a double bond, N-vinyl pyrrolidone and N-isopropylacrylamide.

2. The medical tissue adhesive according to claim 1, characterized in that: The preparation method of the temperature-sensitive polymer is as follows: A mixture of 80-120 parts by weight of an acid anhydride containing a double bond, N-vinyl pyrrolidone, and N-isopropylacrylamide is added to a solvent in a molar ratio of 1:(2-6):(33-37). The mixture is stirred until dissolved. A free radical initiator is then added at a molar ratio of 0.02% of the total monomer amount. The mixture is heated to 60-70°C under a nitrogen atmosphere and stirred for reaction to obtain a temperature-sensitive polymer.

3. The medical tissue adhesive according to claim 1, characterized in that: The acid anhydride containing a double bond is one or more of maleic anhydride, methacrylic anhydride and citraconic anhydride.

4. The medical tissue adhesive according to claim 2, characterized in that: The free radical initiator is azobisisobutyronitrile or azobisisoheptanenitrile.

5. The medical tissue adhesive according to claim 2, characterized in that: The preparation method of the polyglutamic acid grafted thermosensitive polymer is as follows: The polyglutamic acid is dissolved in deionized water, and then the thermosensitive polymer is added. The mass ratio of polyglutamic acid to the thermosensitive polymer is (1.8-2.2):

1. The mixture is stirred until dissolved. The pH is adjusted to 8-9. The mixture is stirred for 5-8 hours. The mixture is dialyzed and freeze-dried to obtain the polyglutamic acid-grafted thermosensitive polymer.

6. The medical tissue adhesive according to claim 1, characterized in that: The added weight portion of the sodium alginate is 1 part, and the added weight portion of the chitosan oligosaccharide is 1 part.

7. A method for preparing the medical tissue adhesive according to any one of claims 1 to 6, characterized in that: It includes the following steps: The raw materials are mixed in proportion, dried at 48-53° C., and then continued to be mixed evenly at this temperature. After cooling, the sample is ground into powder to obtain a medical tissue adhesive.

Images