Modification method and application of medical catheter

Abstract

The invention provides a modification method and application of a medical catheter, the modification method of the medical catheter comprises the following steps: a tertiary amine compound reacts with a lactone compound to prepare a zwitterionic compound, and the main chain of the zwitterionic compound has double bonds; the surface of the initial medical catheter is modified, a first modified medical catheter is prepared, and the surface of the first modified medical catheter is modified with a first functional group which is subjected to amidation reaction; the surface of the first modified medical catheter is modified, a second modified medical catheter is prepared, and the surface of the second modified medical catheter is modified with sulfydryl; the second modified medical catheter and a zwitterionic compound are subjected to a click reaction, and the target medical catheter with the zwitterionic grafted on the surface is prepared. The target medical catheter prepared by the invention has excellent anti-fouling and anti-coagulation characteristics, and the content of leached substances in the target medical catheter is effectively reduced.

Description

Technical Field

[0001] The invention relates to the technical field of biomedical materials, and in particular to a modification method of a medical catheter and application thereof. Background Art

[0002] Hemodialysis is one of the main renal replacement treatments for patients with renal failure. During hemodialysis, a medical catheter is needed to connect to the dialyzer to establish a dialysis pathway. The patient's blood is drawn out of the body through the hemodialysis machine, and the dialyzer is used to remove toxin molecules in the blood to achieve the purpose of purifying the blood.

[0003] At present, the medical catheter widely used in clinical practice is mainly made of polyvinyl chloride, which is extruded by adding plasticizers (such as DEHP) and processing aids. During use, there will be dissolution of plasticizers and other leachable substances, and long-term use will accumulate and produce potential toxicity. In addition, during the dialysis process, direct contact between blood and medical catheters is likely to cause thrombosis, or even coagulation, leading to serious medical accidents. Therefore, in actual dialysis, it is usually necessary to use heparin for anticoagulation, including pre-flushing with heparin before dialysis or adding heparin during dialysis. During the dialysis process, heparin is used for anticoagulation, which makes the dialysis process more complicated, the dosage of heparin is difficult to grasp, and long-term use of heparin can lead to thrombocytopenia and other complications.

[0004] Therefore, it is necessary to perform functional treatment on medical catheters to make them have anticoagulant properties and reduce the dissolution of leachable substances during use of the medical catheters. Summary of the invention

[0005] The present invention aims to solve the above problems existing in the prior art and provides a preparation method and application of a medical catheter having anticoagulant properties and capable of reducing the dissolution of leachable substances during use.

[0006] To solve the above problems, the first aspect of the present invention provides a method for modifying a medical catheter, comprising the following steps:

[0007] The tertiary amine compound reacts with the lactone compound to prepare a zwitterionic compound, wherein the main chain of the zwitterionic compound has a double bond;

[0008] Modifying the surface of an initial medical catheter to obtain a first modified medical catheter, wherein the surface of the first modified medical catheter is modified with a first functional group that undergoes an amidation reaction;

[0009] Modifying the surface of the first modified medical catheter to obtain a second modified medical catheter, wherein the surface of the second modified medical catheter is modified with thiol groups;

[0010] The second modified medical catheter and the zwitterion compound undergo a click reaction to obtain a target medical catheter with zwitterions grafted on the surface.

[0011] Furthermore, the tertiary amine compound reacts with the lactone compound to obtain a zwitterionic compound, including:

[0012] dissolving the tertiary amine compound in an organic solvent to form a uniform first solution;

[0013] The lactone compound is added dropwise to the first solution, and reacted under the protection of an inert gas to obtain the zwitterionic compound.

[0014] Further, the tertiary amine compound is a tertiary amine compound containing a double bond;

[0015] The lactone compound is at least one of 1,3-propane sultone, β-propiolactone, 1,8-naphthalene sultone and 2,4-butane sultone.

[0016] Furthermore, the surface of the initial medical catheter is modified to obtain a first modified medical catheter, comprising:

[0017] Connecting the initial medical catheter to the first modified mixed solution and allowing it to react for a preset time to obtain the first modified medical catheter;

[0018] Wherein, the first modified mixed solution is a mixed solution including an ethanol aqueous solution and a coupling agent, and the coupling agent has the first functional group.

[0019] Furthermore, the reaction temperature of the static reaction is 20°C to 70°C, and the preset time is 2h to 10h;

[0020] The coupling agent is at least one of 3-aminopropyltriethoxysilane, (2,3-epoxypropyloxy)propyltrimethoxysilane, methacryloxypropyltrimethoxysilane and N-(-aminoethyl)-aminopropyltrimethoxysilane.

[0021] Furthermore, the step of modifying the surface of the first modified medical catheter to obtain a second modified medical catheter comprises:

[0022] Connecting the first modified medical catheter to the second modified mixed solution and allowing it to react for a preset time to obtain the second modified medical catheter;

[0023] The second modified mixed solution is a mixed solution including a MES buffer, a condensation reagent and a thiol-reactive agent, and the thiol-reactive agent has a thiol group and the first functional group.

[0024] Further, the first functional group is an amino group or a carboxyl group;

[0025] If the coupling agent has an amino group, the thiolating agent has a carboxyl group and a thiol group; if the coupling agent has a carboxyl group, the thiolating agent has an amino group and a thiol group;

[0026] The thiolating agent is at least one of 2-amino-3-mercaptopropionic acid, β-mercaptoethylamine, β-mercaptopropionic acid, 3-mercaptobenzoic acid, 5-amino-2-mercaptobenzimidazole, and 2-mercapto-4-methyl-5-thiazoleacetic acid;

[0027] The condensation reagent is at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dimethylaminotetrahydropyridinecarboxylate, dicyclohexylcarbodiimide, 4-dimethylaminopyridine, 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate, and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.

[0028] Furthermore, the second modified medical catheter and the zwitterionic compound undergo a click reaction to obtain a target medical catheter with zwitterions grafted on the surface, comprising:

[0029] The second modified medical catheter is placed in the third modified mixed solution, and allowed to react at a first reaction temperature for a first preset time, and then a zwitterionic compound is added to the third modified mixed solution, and allowed to react at a second reaction temperature for a second preset time, to obtain the target medical catheter;

[0030] Wherein, the third modified mixed solution is a mixed solution including MES buffer and a thiol reducing agent.

[0031] Further, the first reaction temperature is 10°C to 40°C, the first preset time is 20min to 60min, the second reaction temperature is 20°C to 70°C, and the second preset time is 2h to 10h;

[0032] The thiol reducing agent is dithiothreitol and / or tris(2-carboxyethyl)phosphine.

[0033] The second aspect of the present invention provides a target medical catheter made by the modification method as described in the first aspect, which is used as a dialyzer catheter.

[0034] The medical catheter modification method of the present invention first modifies the surface of the initial medical catheter by using a coupling agent, modifies the surface of the medical catheter with a first functional group that can undergo an amidation reaction, then causes the first functional group of the thiolating agent to undergo an amidation reaction with the first functional group modified on the surface of the medical catheter, grafts the thiol group to the surface of the medical catheter, and finally causes the double bond on the zwitterionic compound to undergo a click reaction with the thiol group on the surface of the medical catheter, grafts the zwitterionic compound on the surface of the target medical catheter, enables the zwitterionic compound to be more stably connected to the surface of the medical catheter, and the target medical catheter can bind water molecules on its surface through anions and cations in the zwitterionic compound to form a hydration layer, inhibits the adhesion of proteins, cells and some cytokines in the blood, and enables the target medical catheter to have excellent anti-fouling and anticoagulant properties;

[0035] In addition, the zwitterionic compound in the present invention is connected to the surface of the medical catheter in the form of grafting, and does not undergo polymerization reaction on the surface of the medical catheter to form a hydrogel layer, so that the target medical catheter can be subsequently sterilized by conventional medical device sterilization methods, and can be stored and transported in a dry state, so that the target medical catheter can meet the requirements of clinical use;

[0036] In addition, the modification method of the medical catheter provided by the present invention has a simple modification process, mild reaction conditions, high safety during the reaction process, no toxic or harmful solvents are used during the modification process, and the substrate of the medical catheter will not be damaged, which will affect the use of the medical catheter. In addition, during the modification process, by introducing each modified mixed solution into the medical catheter, the leachable substances in the medical catheter can be eluted, the leachable substance content in the target medical catheter is effectively reduced, and a target medical catheter with a low leachable substance content is provided;

[0037] The medical catheter modification method provided in the present invention can flexibly select the zwitterionic compound grafted onto the target medical catheter, and can selectively select the specific type of zwitterionic compound grafted onto the target medical catheter according to actual use requirements to improve the use performance of the target medical catheter. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 A process flow chart for modifying a medical catheter provided in an embodiment of the present invention;

[0039] Figure 2 The result diagram of Experimental Example 1 provided in the embodiments of the present invention;

[0040] Figure 3 This is a result diagram of Test Example 2 provided in an embodiment of the present invention;

[0041] Figure 4 This is a result diagram of Experimental Example 3 provided in an embodiment of the present invention. DETAILED DESCRIPTION

[0042] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, specific embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0043] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other.

[0044] In addition, the terms "comprising", "including", "containing", and "having" are not restrictive, that is, other steps and other components that do not affect the results can be added. Unless otherwise specified, materials, equipment, and reagents are commercially available.

[0045] In addition, although the present invention describes the steps in the preparation in the form of S110, S120, S130, etc., this description is only for ease of understanding, and the form of S110, S120, S130, etc. does not limit the sequence of the steps.

[0046] A first aspect of an embodiment of the present application provides a method for modifying a medical catheter, comprising the following steps:

[0047] Step S110: The tertiary amine compound and the lactone compound react to obtain a zwitterionic compound, wherein the main chain of the zwitterionic compound has a double bond.

[0048] Specifically, a tertiary amine compound is dissolved in an organic solvent to form a uniform first solution, a lactone compound is added dropwise to the first solution, and the reaction is carried out under the protection of an inert gas. After the reaction is completed, the zwitterionic compound is obtained after precipitation, washing and drying. Among them, the zwitterionic compound refers to a polymer compound with cationic and anionic groups in each repeating unit through covalent bonding, so that the zwitterionic compound is electrically neutral. In this embodiment, a zwitterionic compound with a double bond in the main chain is prepared by using a tertiary amine compound and a lactone compound, so that the zwitterionic compound has both a cationic group and an anionic group and a reactive group that can react, so that the zwitterionic compound can directly undergo subsequent modification reactions.

[0049] The main chain of the zwitterionic compound prepared in this embodiment has a structure as shown in Formula (1) or Formula (2), wherein R1 and R2 are both alkyl groups.

[0050]

[0051] Based on the above embodiment, as an optional implementation, the reaction temperature of the tertiary amine compound and the lactone compound is 20° C. to 60° C., and the reaction time is 6 h to 48 h. Therefore, the reaction of the tertiary amine compound and the lactone compound at 20° C. to 60° C. is conducive to improving the reaction activity.

[0052] Based on the above embodiment, as an optional implementation, the dripping rate of the lactone compound added to the first solution can be 0.5 ml / min to 2 ml / min, thereby avoiding the lactone compound being added too quickly, affecting the purity of the zwitterionic compound and increasing the difficulty of subsequent purification.

[0053] On the basis of the above embodiments, as a preferred embodiment, the tertiary amine compound is a tertiary amine compound containing a double bond. Thus, by using a tertiary amine compound containing a double bond, the double bond can be used as a reactive group for subsequent grafting reaction. As an optional embodiment, the tertiary amine compound is at least one of N,N-dimethylacrylamide, N,N-dimethylmethacrylamide, N-[2-(dimethylamino)ethyl]methacrylamide, dimethylaminopropylacrylamide, 3-(N,N-diethylamino)propylacrylamide, N-[2-(5-imidazolyl)ethyl]acrylamide and N-((2-((dimethylamino)methyl)-2H-1,2,3-triazole)methyl)acrylamide.

[0054] In this embodiment, the lactone compound has a sulfonic acid group or a carboxylic acid group. As an optional embodiment, the lactone compound is at least one of 1,3-propane sultone, β-propiolactone, 1,8-naphthalene sultone and 2,4-butane sultone.

[0055] Based on the above embodiments, as a preferred embodiment, the organic solvent can be anhydrous acetonitrile or anhydrous ethanol. Of course, those skilled in the art can also select other organic solvents commonly used in the art.

[0056] Step S120, modifying the surface of the initial medical catheter to obtain a first modified medical catheter, wherein the surface of the first modified medical catheter is modified with a first functional group that undergoes an amidation reaction.

[0057] Specifically, the initial medical catheter is connected to the first modified mixed solution and allowed to stand for a preset reaction time. After the reaction is completed, the inner wall of the medical catheter is rinsed with an ethanol aqueous solution and dried to obtain a first modified medical catheter; wherein the first modified mixed solution is a mixed solution including an ethanol aqueous solution and a coupling agent, the coupling agent has a first functional group, and the first functional group is an amino group or a carboxyl group. In this embodiment, the material of the medical catheter is polyvinyl chloride, and the first modified mixed solution containing a coupling agent is used to modify the medical catheter, so that the surface of the initial medical catheter is modified with the first functional group, which is convenient for the subsequent amidation reaction to graft groups on the surface of the medical catheter.

[0058] Based on the above embodiment, as an optional implementation, the reaction temperature of the static reaction is 20°C to 70°C, and the preset time is 2h to 10h. Therefore, by performing the static reaction under this condition, the initial medical catheter can be fully modified, so that more first functional groups are grafted onto the surface of the initial medical catheter.

[0059] Based on the above embodiment, as an optional implementation, the coupling agent is at least one of 3-aminopropyltriethoxysilane, (2,3-epoxypropyloxy)propyltrimethoxysilane, methacryloxypropyltrimethoxysilane and N-(-aminoethyl)-aminopropyltrimethoxysilane. Of course, the coupling agent can also be selected from other coupling agents having a first functional group.

[0060] In this embodiment, the ethanol aqueous solution in the first modified mixed solution is the solvent, the coupling agent is the solute, the concentration of the ethanol aqueous solution in the first modified mixed solution is 40w / v% (i.e., mass volume concentration) to 95w / v%, and the concentration of the coupling agent in the first modified mixed solution is 0.5w / v% to 5w / v%.

[0061] Step S130, modifying the surface of the first modified medical catheter to obtain a second modified medical catheter, wherein the surface of the second modified medical catheter is modified with thiol groups.

[0062] Specifically, the first modified medical catheter is connected to the second modified mixed solution and allowed to stand for a preset reaction time to obtain the second modified medical catheter; wherein the second modified mixed solution is a mixed solution comprising an MES buffer, a condensation reagent and a thiol reagent, and the thiol reagent has a thiol group and a first functional group. Thus, the first modified medical catheter is subjected to a modification reaction with the second modified mixed solution comprising the thiol reagent, and the first functional group modified on the surface of the first modified medical catheter can undergo an amidation reaction with the first functional group of the thiol reagent, so that the thiol group is grafted on the surface of the second modified medical catheter to obtain a thiol-modified medical catheter.

[0063] More specifically, the condensation reagent is dissolved in the MES buffer solution to form a uniform second solution; the first modified medical catheter is connected and passed into the second solution, the thiol reagent is added, and the reaction is allowed to stand for a preset time under light-proof conditions. After the reaction is completed, the inner wall of the medical catheter is rinsed with deionized water, and the second modified medical catheter is obtained after drying. Thus, by first mixing the condensation reagent and the MES buffer solution uniformly to fully activate the groups on the first modified medical catheter, and then adding the thiol reagent, the groups on the first modified medical catheter can better react with the thiol reagent for amidation.

[0064] Based on the above embodiment, as an optional implementation, the reaction temperature of the static reaction is 20° C. to 70° C., and the reaction time is 2 h to 10 h. Therefore, the amidation reaction is carried out under this condition, the reaction conditions are mild, and it is conducive to improving the activity of the amidation reaction.

[0065] The condensation reagent can cause a condensation reaction, and the condensation reagent mainly links the acid and the amine together, promoting the first functional group modified on the surface of the first modified medical catheter to undergo a condensation reaction with the first functional group of the thiol-reactive agent, generating a macromolecular structure with a thiol group, thereby enabling the thiol group to be grafted onto the surface of the second modified medical catheter. As an optional embodiment, the condensation reagent is at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dimethylaminotetrahydropyridinecarboxylate, dicyclohexylcarbodiimide, 4-dimethylaminopyridine, 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate and benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. In this embodiment, the concentration of the condensation reagent in the second modified mixed solution is 0.05 w / v% to 1 w / v%.

[0066] The full name of MES buffer solution is 2-morpholineethanesulfonic acid, also known as 4-morpholineethanesulfonic acid. MES buffer solution is a zwitterionic buffer solution. MES buffer solution is effective in the pH range of 5.5 to 7.7. As a Good's buffer, it can offset or reduce the effect of an external strong acid or strong base on the pH of the solution to a certain extent, so as to keep the pH value of the solution relatively stable. In this embodiment, by adding MES buffer solution, the pH value of the entire reaction system during the amidation reaction can be stabilized.

[0067] The thiol reagent has a thiol group and a first functional group, wherein the thiol group is also called a thiol group or a thiol group, which is a negative monovalent functional group composed of a sulfur atom and a hydrogen atom connected, and the chemical formula is -SH. Different groups are connected to the thiol end, and the organic matter belongs to different categories, such as thiol (R-SH) and thiophenol (Ar-SH). In this embodiment, when selecting the specific type of the thiol reagent, it is necessary to match the specific type of the coupling agent in step S120. Specifically, if the first group of the coupling agent is an amino group, the thiol reagent has a carboxyl group and a thiol group; if the first group of the coupling agent is a carboxyl group, the thiol reagent has an amino group and a thiol group. In this way, it can be ensured that the first functional group modified on the surface of the first modified medical catheter undergoes an amidation reaction with the first functional group of the thiol reagent. As an optional embodiment, the thiolating agent is at least one of 2-amino-3-mercaptopropionic acid, β-mercaptoethylamine, β-mercaptopropionic acid, 3-mercaptobenzoic acid, 5-amino-2-mercaptobenzimidazole and 2-mercapto-4-methyl-5-thiazoleacetic acid, and the concentration of the thiol group in the thiolating agent is 0.1 to 5 w / v%.

[0068] Based on the above embodiment, as an optional implementation, the reaction temperature of the static reaction is 20° C. to 70° C., and the reaction time is 2 h to 10 h. Therefore, the amidation reaction is carried out under this condition, the reaction conditions are mild, and it is conducive to improving the activity of the amidation reaction.

[0069] Step S140: The second modified medical catheter and the zwitterion compound undergo a click reaction to obtain a target medical catheter with zwitterions grafted on the surface.

[0070] Specifically, the second modified medical catheter is connected to the third modified mixed solution, and the solution is allowed to react at a first reaction temperature for a first preset time, and then a zwitterionic compound is added to the third modified mixed solution, and the solution is allowed to react at a second reaction temperature for a second preset time to obtain a target medical catheter; wherein the third modified mixed solution is a mixed solution including a MES buffer solution and a thiol reducing agent. Therefore, in this embodiment, the third modified mixed solution containing the thiol reducing agent is first reacted with the second modified medical catheter, so that the disulfide bond formed by the thiol group during the modification process can be reduced to a thiol group, so that the disulfide bond is fully reacted to form a thiol group, and then the zwitterionic compound is added, which can improve the yield and efficiency of the click reaction between the thiol group and the zwitterionic compound, and avoid the disulfide bond formed by the thiol group during the modification process affecting the yield and efficiency of the click reaction, thereby affecting the use performance of the target medical catheter; the thiol group grafted on the surface of the second modified medical catheter undergoes a click reaction with the double bond on the zwitterionic compound to obtain a zwitterion-grafted target medical catheter, and the zwitterionic grafted target medical catheter can form a hydration layer by combining water molecules on the surface of the target medical catheter through the anions and cations of the zwitterionic compound, thereby inhibiting the adhesion of proteins, cells and some cytokines in the blood, so that the target medical catheter has excellent anti-fouling and anticoagulant properties.

[0071] Based on the above embodiment, as an optional implementation, the thiol reducing agent is dithiothreitol and / or tris(2-carboxyethyl)phosphine. The concentration of the thiol reducing agent in the third modified mixed solution is 0.05 w / v% to 5% w / v%. Therefore, the thiol reducing agent is selected from the above category and controlled within the above concentration range, which can fully reduce the disulfide bonds formed by the thiol group during the modification process to thiol groups, which is conducive to further improving the yield of the click reaction.

[0072] Based on the above embodiment, as an optional implementation manner, the amount of the zwitterionic compound added is 0.1 w / v % to 10 w / v % of the total amount of the third modified mixed solution and the zwitterionic compound.

[0073] Based on the above embodiment, as an optional implementation, the first reaction temperature is 10°C to 40°C, and the first preset time is 20min to 60min, so that the reaction at this temperature is conducive to the thiol reducing agent to fully reduce the disulfide bonds formed by the thiol group during the modification process to thiol groups. The second reaction temperature is 20°C to 70°C, and the second preset time is 2h to 10h, so that the reaction at this temperature is conducive to improving the reactivity of the thiol group and the double bond on the zwitterionic compound to undergo a click reaction.

[0074] Based on the above embodiment, as an optional implementation, after adding the zwitterionic compound to the third modified mixed solution, before reacting at the second reaction temperature for the second preset time, it also includes adding an alkaline substance to adjust the pH value of the reaction solution (i.e., the third modified mixed solution and the zwitterionic compound), and adjusting the pH value of the reaction solution to a range of 6 to 8. The double bonds on the thiol group and the zwitterionic compound react within this pH range, which is conducive to improving the yield of the click reaction. As an optional implementation, the alkaline substance is a sodium hydroxide solution, and the alkaline substance can also be a potassium hydroxide solution.

[0075] The modification method of the medical catheter provided in this embodiment first modifies the surface of the initial medical catheter by using a coupling agent, modifies the surface of the medical catheter with a first functional group that can undergo an amidation reaction, then causes the first functional group of the thiolating agent to undergo an amidation reaction with the first functional group modified on the surface of the medical catheter, grafts the thiol group to the surface of the medical catheter, and finally causes the double bond on the zwitterionic compound to undergo a click reaction with the thiol group on the surface of the medical catheter, grafts the zwitterionic compound on the surface of the target medical catheter, and enables the zwitterionic compound to be more stably connected to the surface of the medical catheter. The target medical catheter can bind water molecules on its surface through anions and cations in the zwitterionic compound to form a hydration layer, thereby inhibiting the adhesion of proteins, cells and some cytokines in the blood, so that the target medical catheter has excellent anti-fouling and anticoagulant properties.

[0076] In addition, in this embodiment, the zwitterionic compound is connected to the surface of the medical catheter in the form of grafting, and no polymerization reaction occurs on the surface of the medical catheter to form a hydrogel layer, so that the target medical catheter can be subsequently sterilized by conventional medical device sterilization methods, and can be stored and transported in a dry state, so that the target medical catheter can meet the requirements of clinical use;

[0077] In addition, the modification method of the medical catheter provided in this embodiment has a simple modification process, mild reaction conditions, high safety during the reaction process, no toxic or harmful solvents are used during the modification process, and the substrate of the medical catheter will not be damaged, which will affect the use of the medical catheter. In addition, during the modification process, by introducing each modified mixed solution into the medical catheter, the leachable substances in the medical catheter can be eluted, the leachable substance content in the target medical catheter is effectively reduced, and a target medical catheter with a low leachable substance content is provided;

[0078] The modification method of the medical catheter provided in this embodiment can flexibly select the zwitterionic compound grafted onto the target medical catheter, and can selectively select the specific type of the zwitterionic compound grafted onto the target medical catheter according to actual use requirements to improve the use performance of the target medical catheter. For example, if the charge on the surface of the target medical catheter is to be increased, a zwitterionic compound with strong acidity can be selected; if the strength of the surface of the target medical catheter is to be enhanced, a zwitterionic compound with a benzene ring or an imidazole group can be selected.

[0079] The second aspect of this embodiment provides a catheter for a dialyzer, which is a target medical catheter prepared by the modification method described in the first aspect. Therefore, using the target medical catheter prepared in this embodiment as a catheter for a dialyzer is beneficial to improving the anticoagulant performance during the dialysis process, reducing the dissolution of leachable substances during the dialysis process, and improving the safety of the dialyzer.

[0080] In order to further explain the present invention in detail, the present invention will be further explained in conjunction with specific examples. The experimental methods used in the examples of the present invention are conventional methods unless otherwise specified; the materials, reagents, etc. used in the examples of the present invention are purchased from the market unless otherwise specified.

[0081] Example 1

[0082] This embodiment provides a method for modifying a medical catheter, comprising the following steps:

[0083] (1) Weigh 4.96 g of N,N-dimethylacrylamide and dissolve it in 150 mL of anhydrous acetonitrile to form a uniform first solution; use a constant pressure funnel to dropwise add 4.5 g of 1,3-propane sultone into the first solution at a rate of 1 ml / min, fill with nitrogen to expel oxygen for protection, and react at 40° C. for 12 hours; after the reaction is completed, pour out the supernatant, add anhydrous ether as a precipitant, and repeatedly wash 3 times, and transfer to a hollow drying oven for drying to obtain a dimethylacrylamide sulfonic acid zwitterionic compound in the form of a white powder.

[0084] (2) Prepare 300 ml of a 46% ethanol-water mixed solution, add 5 g of a coupling agent 3-aminopropyltriethoxysilane, mix well, and obtain a first modified mixed solution; connect the initial medical catheter to the first modified mixed solution, seal both ends of the medical catheter, place it under a reaction condition of 65° C., and react for 6 hours; after the reaction is completed, use a 46% ethanol aqueous solution to rinse the inner wall of the medical catheter 3 times, blow dry with compressed air, and obtain a first modified medical catheter, wherein the inner wall surface of the first modified medical catheter is modified with amino groups.

[0085] (3) 300 ml of a 50 mmol / L MES buffer solution with a pH of 6.8 was prepared, 1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added to form a uniform second solution, the first modified medical catheter was connected and introduced into the second solution, after reaction activation for 30 min, 1 g of 2-amino-3-mercaptopropionic acid was added, both ends of the first modified medical catheter were sealed, and the solution was placed in a dark place at 37° C. for reaction for 8 hours. After the reaction was completed, the inner wall of the medical catheter was washed three times with deionized water and dried with compressed air to obtain a second modified medical catheter, the inner wall surface of which was modified with thiol groups.

[0086] (4) Prepare 300 ml of 50 mmol / L MES buffer solution with a pH of 6.8, add 3 g of thiol reducing agent dithiothreitol DTT, mix thoroughly to obtain a third modified mixed solution, connect the second modified medical catheter and pass it into the third modified mixed solution, seal both ends of the second modified medical catheter, place it in a dark place at 37° C. for reaction for 30 min, then add 5.4 g of the dimethyl acrylamide sulfonic acid zwitterionic compound prepared in step (1), add 0.5 mol / L sodium hydroxide solution to adjust the pH of the reaction solution to 7.4, place it in a dark place at 37° C. for reaction for 8 hours, and after the reaction is completed, use deionized water to clean the inner wall of the medical catheter for 3 times, blow dry with compressed air to obtain a target medical catheter, which is a medical catheter with a low leachable content grafted with zwitterionic modified on the inner wall surface.

[0087] Example 2

[0088] This embodiment provides a method for modifying a medical catheter, comprising the following steps:

[0089] (1) Weigh 4.96 g of N,N-dimethylacrylamide and dissolve it in 150 mL of anhydrous acetonitrile to form a uniform first solution; use a constant pressure funnel to dropwise add 3.6 g of β-propiolactone into the first solution at a rate of 1 ml / min, fill with nitrogen to expel oxygen for protection, and react at 40° C. for 12 hours; after the reaction is completed, pour out the supernatant, add anhydrous ether as a precipitant, and repeatedly wash 3 times, and transfer to a hollow drying oven for drying to obtain a dimethylacrylamide carboxylic acid zwitter ion compound in the form of a white powder.

[0090] (2) Prepare 300 ml of a 46% ethanol-water mixed solution, add 7 g of a coupling agent (2,3-epoxypropyl)propyltrimethoxysilane, mix well, and obtain a first modified mixed solution; connect the initial medical catheter to the first modified mixed solution, seal both ends of the medical catheter, place it under a reaction condition of 65° C., and react for 6 hours; after the reaction is completed, use a 46% ethanol aqueous solution to rinse the inner wall of the medical catheter 3 times, blow dry with compressed air, and obtain a first modified medical catheter, wherein the inner wall surface of the first modified medical catheter is modified with carboxyl groups.

[0091] (3) 300 ml of a 50 mmol / L MES buffer solution with a pH of 6.8 was prepared, and 1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added to form a uniform second solution. The first modified medical catheter was connected and introduced into the prepared second solution. After the reaction was activated for 30 min, 2 g of 5-amino-2-mercaptobenzimidazole was added, and both ends of the first modified medical catheter were sealed. The catheter was placed in a dark place at 37° C. for reaction for 8 hours. After the reaction was completed, the inner wall of the medical catheter was washed with deionized water for 3 times and dried with compressed air to obtain a second modified medical catheter, wherein the inner wall of the second modified medical catheter was modified with a thiol group.

[0092] (4) Prepare 300 ml of 50 mmol / L MES buffer solution with a pH of 6.8, add 3 g of thiol reducing agent dithiothreitol DTT, mix thoroughly to obtain a third modified mixed solution, connect the second modified medical catheter and pass it into the third modified mixed solution, seal both ends of the second modified medical catheter, place it in a dark place at 37° C. for reaction for 30 min, then add 4.8 g of the dimethylacrylamide carboxylic acid zwitterionic compound obtained in step (1), add 0.5 mol / L sodium hydroxide solution to adjust the pH of the reaction solution to 7.4, place it in a dark place at 37° C. for reaction for 8 hours, and after the reaction is completed, use deionized water to clean the inner wall of the medical catheter for 3 times, blow dry with compressed air to obtain a target medical catheter, which is a medical catheter with low leachable content grafted with zwitterionic modified on the inner wall surface.

[0093] Example 3

[0094] This embodiment provides a method for modifying a medical catheter, comprising the following steps:

[0095] (1) Weigh 10.42 g of N-((2-((dimethylamino)methyl)-2H-1,2,3-triazole)methyl)acrylamide and dissolve it in 150 mL of anhydrous acetonitrile to form a uniform first solution; add 4.5 g of 1,3-propanesultone dropwise into the first solution at a rate of 1 ml / min using a constant pressure funnel, fill with nitrogen to expel oxygen for protection, and react at 40° C. for 12 hours; after the reaction is completed, pour out the supernatant, add anhydrous ether as a precipitant, wash repeatedly for 3 times, and transfer to a hollow drying oven for drying to obtain a dimethylaminomethacrylamidesulfonic acid triazole zwitterionic compound in the form of a white powder.

[0096] (2) Prepare 300 ml of a 46% ethanol-water mixed solution, add 5 g of a coupling agent 3-aminopropyltriethoxysilane, mix well, and obtain a first modified mixed solution; connect the initial medical catheter to the first modified mixed solution, seal both ends of the medical catheter, place it under a reaction condition of 65° C., and react for 6 hours; after the reaction is completed, use a 46% ethanol aqueous solution to rinse the inner wall of the medical catheter 3 times, blow dry with compressed air, and obtain a first modified medical catheter, wherein the inner wall surface of the first modified medical catheter is modified with amino groups.

[0097] (3) 300 ml of a 50 mmol / L MES buffer solution with a pH of 6.8 was prepared, 1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added to form a uniform second solution, the first modified medical catheter was connected and introduced into the second solution, after reaction activation for 30 min, 2 g of 3-mercaptobenzoic acid was added, both ends of the first modified medical catheter were sealed, and the solution was placed in a dark place at 37° C. for reaction for 8 hours. After the reaction was completed, the inner wall of the medical catheter was washed three times with deionized water and dried with compressed air to obtain a second modified medical catheter, the inner wall surface of which was modified with thiol groups.

[0098] (4) Prepare 300 ml of 50 mmol / L MES buffer solution with a pH of 6.8, add 3 g of thiol reducing agent dithiothreitol DTT, mix thoroughly to obtain a third modified mixed solution, connect the second modified medical catheter and pass it into the third modified mixed solution, seal both ends of the second modified medical catheter, place it in a dark place at 37° C. for reaction for 30 min, then add 8.7 g of the dimethylaminomethylacrylamidesulfonic acid triazole zwitterionic compound prepared in step (1), add 0.5 mol / L sodium hydroxide solution to adjust the pH of the reaction solution to 7.4, place it in a dark place at 37° C. for reaction for 8 hours, and after the reaction is completed, use deionized water to clean the inner wall of the medical catheter 3 times, blow dry with compressed air to obtain a target medical catheter, which is a medical catheter with a low leachable content grafted with zwitterionic modified on the inner wall surface.

[0099] Test Example 1

[0100] The target medical catheters prepared in Examples 1 to 3 were taken respectively, and the initial medical catheters in Examples 1 to 3 were used as controls, and activated partial prothrombin time (APTT) tests were performed on each medical catheter. The specific test steps are as follows: venous blood was centrifuged and the supernatant plasma was taken for standby use, an APTT detection kit was selected for the test, the activator in the APTT detection kit was added to the pre-warmed plasma containing each medical catheter, and incubated at 37°C for 5 minutes, and then the pre-warmed CaCl2 reagent was added, and the coagulation time was measured by a blood coagulation analyzer, and the coagulation time was read.

[0101] The results of APTT test are as follows Figure 2 As shown by Figure 2 It can be seen that the APTT value of the modified medical catheter in Example 1 is increased from 35s to 370s, the APTT value of the modified medical catheter in Example 2 is increased from 34s to 355s, and the APTT value of the modified medical catheter in Example 3 is increased from 36s to 366s. It can be shown that after the medical catheter is modified by the modification method of the medical catheter provided by the present invention, the anticoagulant performance of the medical catheter is greatly improved, so that the target medical catheter has excellent anticoagulant performance.

[0102] Test Example 2

[0103] The target medical catheters prepared in Examples 1 to 3 were taken respectively, and the initial medical catheters in Examples 1 to 3 were used as controls, and bovine serum albumin (BSA) adsorption tests were performed on each medical catheter. The specific test steps are as follows:

[0104] One end of each medical catheter was clamped, and 50 ml of MES buffer solution with a concentration of 1 mg / mL BSA was added. After standing for 12 hours, the characteristic absorption peak of BSA was measured by UV spectrophotometer. A standard curve was prepared for simultaneous testing, and the BSA attachment amount of the medical catheters before and after modification in Examples 1 to 3 was calculated.

[0105] The results of BSA adsorption test are as follows Figure 3 As shown by Figure 3It can be seen that the adsorption rate of BSA of the modified medical catheter in Example 1 is reduced from 76% to 12%, which is 84.2% lower than the initial medical catheter adsorption rate before modification; the adsorption rate of BSA of the modified medical catheter in Example 2 is reduced from 83% to 15%, which is 81.9% lower than the initial medical catheter adsorption rate before modification; the adsorption rate of BSA of the modified medical catheter in Example 3 is reduced from 78% to 13%, which is 83.3% lower than the initial medical catheter adsorption rate before modification. It can be explained that after the medical catheter is modified by the modification method of the medical catheter provided by the present invention, the adhesion of proteins, cells and some cytokines in the blood can be inhibited, thereby facilitating the improvement of the anti-fouling and anti-coagulation properties of the target medical catheter.

[0106] Test Example 3

[0107] The target medical catheters prepared in Examples 1 to 3 were taken respectively, and the initial medical catheters in Examples 1 to 3 were used as controls to test the leachable content of each medical catheter. The specific test steps are as follows:

[0108] Prepare 500 ml of a 46% ethanol-water mixed solution, connect it to various medical catheters using a circulation pump, circulate it at 37° C. for 5.5 hours, take samples and measure the DEHP concentration in the extract using a high performance liquid chromatograph.

[0109] The test results of leachable content are as follows: Figure 4 As shown by Figure 4 It can be seen that the DEHP concentration in the modified medical catheter extract of Example 1 is reduced from 58.3 μg / ml to 26.8 μg / ml, the DEHP concentration in the modified medical catheter extract of Example 2 is reduced from 57.6 μg / ml to 25.5 μg / ml, and the DEHP concentration in the modified medical catheter extract of Example 3 is reduced from 56.8 μg / ml to 25.9 μg / ml. It can be shown that after the medical catheter is modified by the modification method of the medical catheter provided by the present invention, the content of leachables in the target medical catheter can be effectively reduced, thereby providing a target medical catheter with low leachable content.

[0110] Although the disclosure is disclosed as above, the protection scope of the disclosure is not limited thereto. Those skilled in the art may make various changes and modifications without departing from the spirit and scope of the disclosure, and these changes and modifications will fall within the protection scope of the present invention.

Claims

1. A method for modifying a medical catheter, characterized in that: The steps include: The tertiary amine compound reacts with the lactone compound to prepare a zwitterionic compound, wherein the main chain of the zwitterionic compound has a double bond; Modifying the surface of an initial medical catheter to obtain a first modified medical catheter, wherein the surface of the first modified medical catheter is modified with a first functional group that undergoes an amidation reaction; Modifying the surface of the first modified medical catheter to obtain a second modified medical catheter, wherein the surface of the second modified medical catheter is modified with thiol groups; The second modified medical catheter and the zwitterion compound undergo a click reaction to obtain a target medical catheter with zwitterions grafted on the surface.

2. The method for modifying a medical catheter according to claim 1, characterized in that: The tertiary amine compound reacts with the lactone compound to prepare a zwitterionic compound, including: dissolving the tertiary amine compound in an organic solvent to form a uniform first solution; The lactone compound is added dropwise to the first solution, and reacted under the protection of an inert gas to obtain the zwitterionic compound.

3. The method for modifying a medical catheter according to claim 1, characterized in that: The tertiary amine compound is a tertiary amine compound containing a double bond; The lactone compound is at least one of 1,3-propane sultone, β-propiolactone, 1,8-naphthalene sultone and 2,4-butane sultone.

4. The method for modifying a medical catheter according to claim 1, characterized in that: The process of modifying the surface of the initial medical catheter to obtain a first modified medical catheter comprises: Connecting the initial medical catheter to the first modified mixed solution and allowing it to react for a preset time to obtain the first modified medical catheter; Wherein, the first modified mixed solution is a mixed solution including an ethanol aqueous solution and a coupling agent, and the coupling agent has the first functional group.

5. The method for modifying a medical catheter according to claim 4, characterized in that: The reaction temperature of the static reaction is 20°C to 70°C, and the preset time is 2h to 10h; The coupling agent is at least one of 3-aminopropyltriethoxysilane, (2,3-epoxypropyloxy)propyltrimethoxysilane, methacryloxypropyltrimethoxysilane and N-(-aminoethyl)-aminopropyltrimethoxysilane.

6. The method for modifying a medical catheter according to claim 4, characterized in that: The step of modifying the surface of the first modified medical catheter to obtain a second modified medical catheter comprises: Connecting the first modified medical catheter to the second modified mixed solution and allowing it to react for a preset time to obtain the second modified medical catheter; The second modified mixed solution is a mixed solution including a MES buffer, a condensation reagent and a thiol-reactive agent, and the thiol-reactive agent has a thiol group and the first functional group.

7. The method for modifying a medical catheter according to claim 6, characterized in that: The first functional group is an amino group or a carboxyl group; If the coupling agent has an amino group, the thiolating agent has a carboxyl group and a thiol group; if the coupling agent has a carboxyl group, the thiolating agent has an amino group and a thiol group; The thiolating agent is at least one of 2-amino-3-mercaptopropionic acid, β-mercaptoethylamine, β-mercaptopropionic acid, 3-mercaptobenzoic acid, 5-amino-2-mercaptobenzimidazole, and 2-mercapto-4-methyl-5-thiazoleacetic acid; The condensation reagent is at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dimethylaminotetrahydropyridinecarboxylate, dicyclohexylcarbodiimide, 4-dimethylaminopyridine, 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate, and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.

8. The method for modifying a medical catheter according to claim 1, characterized in that: The second modified medical catheter and the zwitterionic compound undergo a click reaction to obtain a target medical catheter with zwitterions grafted on the surface, comprising: The second modified medical catheter is placed in the third modified mixed solution, and allowed to react at a first reaction temperature for a first preset time, and then a zwitterionic compound is added to the third modified mixed solution, and allowed to react at a second reaction temperature for a second preset time, to obtain the target medical catheter; Wherein, the third modified mixed solution is a mixed solution including MES buffer and a thiol reducing agent.

9. The method for modifying a medical catheter according to claim 8, characterized in that: The first reaction temperature is 10°C to 40°C, the first preset time is 20min to 60min, the second reaction temperature is 20°C to 70°C, and the second preset time is 2h to 10h; The thiol reducing agent is dithiothreitol and / or tris(2-carboxyethyl)phosphine.

10. A target medical catheter obtained by the modification method according to any one of claims 1 to 9, which is used as a dialyzer catheter.

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